[{"result":{"data":{"method":"DeepDiveWithReviewer","timestamp":"2026-03-12 20:04:55.134079","user_id":"TWuFn4411RQmRel9PvGECQmyve8ZNzNd","user_name":"Daniel Clarke","published":true,"input":{"input":"KLF4 & Diabetic Nephropathy"},"output":{"input":{"id":"295e4d62-0ba7-4af5-823b-0911b8cda7f5","key":"input","value":"KLF4 & Diabetic Nephropathy","timestamp":"2026-03-12T20:04:58.612412","runnable_id":"b0cf41c5-0708-45d1-b450-846f2bc97202"},"output":{"id":"3215fcfe-0701-41c9-826b-11b75a242d05","key":"output","value":"# KLF4 in diabetic kidney disease: preclinical mechanisms and translational leads\n\nMultiple cellular, animal and patient‑level studies indicate KLF4 is downregulated in diabetic kidney disease; preclinical (cellular and animal) data show restoring KLF4 can preserve podocyte, tubular and endothelial phenotypes via complementary mechanisms. In podocytes KLF4 maintains epithelial identity and nephrin expression through epigenetic (DNA‑methylation) remodeling, and KLF4 loss worsens proteinuria, whereas KLF4 overexpression reduces albuminuria and podocyte apoptosis and activates autophagy via inhibition of the mTOR/S6K axis[^1][^3]. In proximal tubule cells KLF4 dampens TGF‑β1–driven inflammatory mediators (e.g., MIF, MCP‑1), with less consistent effects reported on extracellular matrix proteins[^2]. A KLF4–p62 axis has been implicated in protecting vascular endothelial cells by promoting autophagy through mTOR/S6K signaling[^4]. Bioinformatic analyses implicate ferroptosis pathways in diabetic nephropathy, patient studies report altered KLF4 expression and promoter methylation in diabetes, and experimental work shows berberine reduces KLF4 promoter methylation and ferroptosis and improves renal outcomes in mice—supporting epigenetic‑targeting approaches; these findings remain to be validated in humans[^5][^7][^6]. Smaller interventional preclinical studies (e.g., Δ9‑THC in diabetic rats) and reviews highlighting mitochondrial/mitophagy dysfunction further place KLF4 at the intersection of epigenetic, autophagic and redox/ferroptotic pathways relevant to DKD, supporting additional human‑level validation[^8][^9].\n\n[^1]: Hayashi K, Sasamura H, Nakamura M, et al. KLF4‑dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. J Clin Invest. 2014. doi:10.1172/JCI69557  \n[^2]: Mreich E, Chen X‑M, Zaky A, et al. The role of Krüppel‑like factor 4 in transforming growth factor‑β‑induced inflammatory and fibrotic responses in human proximal tubule cells. Clin Exp Pharmacol Physiol. 2015. doi:10.1111/1440‑1681.12405  \n[^3]: Gong J, Zhan H, Li Y, et al. Krüppel‑like factor 4 ameliorates diabetic kidney disease by activating autophagy via the mTOR pathway. Mol Med Rep. 2019. doi:10.3892/mmr.2019.10585  \n[^4]: Wang X, Su W, Ma M, et al. The KLF4‑p62 axis prevents vascular endothelial cell injury via the mTOR/S6K pathway and autophagy in diabetic kidney disease. Endokrynol Pol. 2022. doi:10.5603/EP.a2022.0072  \n[^5]: Hu Y, Liu S, Liu W, et al. Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches. PLoS One. 2021. doi:10.1371/journal.pone.0259436  \n[^6]: Cai S, Zhu H, Chen L, et al. Berberine Inhibits KLF4 Promoter Methylation and Ferroptosis to Ameliorate Diabetic Nephropathy in Mice. Chem Res Toxicol. 2024. doi:10.1021/acs.chemrestox.4c00263  \n[^7]: Coskun ZM, Ersoz M, Adas M, et al. Kruppel‑Like Transcription Factor‑4 Gene Expression and DNA Methylation Status in Type 2 Diabetes and Diabetic Nephropathy Patients. Arch Med Res. 2019. doi:10.1016/j.arcmed.2019.05.012  \n[^8]: Yanar K, Coskun ZM, Beydogan AB, et al. The effects of delta‑9‑tetrahydrocannabinol on Krüppel‑like factor‑4 expression, redox homeostasis, and inflammation in the kidney of diabetic rat. J Cell Biochem. 2019. doi:10.1002/jcb.28903  \n[^9]: Pavlović N, Križanac M, Kumrić M, et al. Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression. Cells. 2025. doi:10.3390/cells14110794","timestamp":"2026-03-12T20:06:28.646209","runnable_id":"b0cf41c5-0708-45d1-b450-846f2bc97202"},"prompt":{"id":"fb3d78c3-ecd2-4f39-beff-b1ad29f1df76","key":"prompt","value":[{"role":"user","content":"# Our Summary\n# KLF4 in diabetic nephropathy: roles, mechanisms and therapeutic leads\n\nCollectively, studies across cellular, animal and human samples indicate that KLF4 is downregulated in diabetic kidney disease and that restoring KLF4 activity preserves glomerular and tubular function through multiple mechanisms: in podocytes KLF4 maintains epithelial identity and nephrin expression via epigenetic (DNA methylation) remodeling and its loss worsens proteinuria, while KLF4 overexpression reduces albuminuria and podocyte apoptosis and activates autophagy by inhibiting the mTOR/S6K axis[^1][^3]. In proximal tubule cells KLF4 dampens TGF‑β1–driven inflammatory responses (MIF, MCP‑1) though effects on extracellular matrix proteins were less clear, and a KLF4–p62 axis has been implicated in protecting endothelial cells via mTOR‑dependent autophagy[^2][^4]. Bioinformatic and patient‑level studies additionally link KLF4 to regulated cell‑death programs relevant to diabetic nephropathy (ferroptosis/“iron death”) and report altered KLF4 expression and promoter methylation in diabetes, supporting translational approaches that target KLF4 epigenetic regulation (e.g., berberine reduces KLF4 promoter methylation and ferroptosis and improves renal outcomes in mice) as well as pharmacologic/biologic modulation in preclinical models[^5][^7][^6]. Smaller interventional studies (e.g., THC) and reviews emphasizing mitochondrial/mitophagy dysfunction further suggest KLF4 sits at the intersection of epigenetic, autophagic and redox/ferroptotic pathways relevant to DKD, making it a promising mechanistic and therapeutic target that warrants further human validation[^8][^9].\n\n[^1]: Hayashi K, Sasamura H, Nakamura M, et al. KLF4‑dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. J Clin Invest. 2014. doi:10.1172/JCI69557  \n[^2]: Mreich E, Chen X‑M, Zaky A, et al. The role of Krüppel‑like factor 4 in transforming growth factor‑β‑induced inflammatory and fibrotic responses in human proximal tubule cells. Clin Exp Pharmacol Physiol. 2015. doi:10.1111/1440‑1681.12405  \n[^3]: Gong J, Zhan H, Li Y, et al. Krüppel‑like factor 4 ameliorates diabetic kidney disease by activating autophagy via the mTOR pathway. Mol Med Rep. 2019. doi:10.3892/mmr.2019.10585  \n[^4]: Wang X, Su W, Ma M, et al. The KLF4‑p62 axis prevents vascular endothelial cell injury via the mTOR/S6K pathway and autophagy in diabetic kidney disease. Endokrynol Pol. 2022. doi:10.5603/EP.a2022.0072  \n[^5]: Hu Y, Liu S, Liu W, et al. Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches. PLoS One. 2021. doi:10.1371/journal.pone.0259436  \n[^6]: Cai S, Zhu H, Chen L, et al. Berberine Inhibits KLF4 Promoter Methylation and Ferroptosis to Ameliorate Diabetic Nephropathy in Mice. Chem Res Toxicol. 2024. doi:10.1021/acs.chemrestox.4c00263  \n[^7]: Coskun ZM, Ersoz M, Adas M, et al. Kruppel‑Like Transcription Factor‑4 Gene Expression and DNA Methylation Status in Type 2 Diabetes and Diabetic Nephropathy Patients. Arch Med Res. 2019. doi:10.1016/j.arcmed.2019.05.012  \n[^8]: Yanar K, Coskun ZM, Beydogan AB, et al. The effects of delta‑9‑tetrahydrocannabinol on Krüppel‑like factor‑4 expression, redox homeostasis, and inflammation in the kidney of diabetic rat. J Cell Biochem. 2019. doi:10.1002/jcb.28903  \n[^9]: Pavlović N, Križanac M, Kumrić M, et al. Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression. Cells. 2025. doi:10.3390/cells14110794"},{"role":"user","content":"# Feedback\nOverall this is a useful, well‑synthesised draft, but it needs tightening to avoid small attribution and overgeneralisation errors. Concise points and a corrected one‑paragraph summary follow.\n\nMain problems to fix\n- Citation placement: some claims mix cell types and citations (e.g., KLF4–p62/ endothelial autophagy is supported by [^4], not [^2]; [^2] is proximal‑tubule TGF‑β work). Separate citations by the specific cell/type claim.  \n- Tone/strength: several sentences imply clinical validation or broad preservation of renal function without always specifying preclinical/cellular evidence. Add qualifiers (e.g., \"preclinical/cell/animal data show…\") where appropriate.  \n- Specificity: state which findings are epigenetic, autophagic, inflammatory or ferroptotic and cite accordingly rather than grouping loosely.  \n- Minor wording: use consistent terminology (e.g., ferroptosis rather than only the informal “iron death”), and avoid implying causality in human disease beyond what the patient‑level studies show.\n\nRevised concise summary (citations corrected and phrasing tightened)\nMultiple cellular, animal and patient‑level studies indicate KLF4 is downregulated in diabetic kidney disease, and preclinical data show restoring KLF4 can preserve podocyte, tubular and endothelial phenotypes through complementary mechanisms. In podocytes KLF4 maintains epithelial identity and nephrin expression via epigenetic (DNA‑methylation) remodeling and loss of KLF4 worsens proteinuria; KLF4 overexpression reduces albuminuria and podocyte apoptosis and activates autophagy via inhibition of the mTOR/S6K axis[^1][^3]. In proximal tubule cells KLF4 dampens TGF‑β1–driven inflammatory mediators (MIF, MCP‑1), while effects on extracellular matrix proteins are less clear[^2]. A KLF4–p62 axis has been implicated in protecting vascular endothelial cells via mTOR‑dependent autophagy[^4]. Bioinformatic analyses implicate ferroptosis pathways in diabetic nephropathy, and patient studies report altered KLF4 expression and promoter methylation in diabetes; experimental work shows berberine reduces KLF4 promoter methylation and ferroptosis and improves renal outcomes in mice[^5][^7][^6]. Smaller interventional studies (e.g., THC in diabetic rats) and reviews emphasizing mitochondrial/mitophagy dysfunction further place KLF4 at the intersection of epigenetic, autophagic and redox/ferroptotic pathways relevant to DKD, supporting further validation in human studies[^8][^9].\n\nConcise actionable edits you can apply to the original paragraph\n- Move the [^4] citation to the clause about endothelial KLF4–p62 and leave [^2] for proximal tubule claims.  \n- Precede broad claims about \"preserving renal function\" with “preclinical data show” (or similar).  \n- Replace informal phrase “iron death” with “ferroptosis” (or write both once: ferroptosis (“iron death”)).  \n- If you state “links KLF4 to ferroptosis” ensure that the bioinformatic source explicitly reports KLF4 (otherwise phrase as “ferroptosis pathways implicated in DN and KLF4 methylation/expression altered in patients”)."},{"role":"user","content":"In light of the feedback, improve our paragraph summary.\nOutput in markdown, start with an informative title, use footnote formatting (e.g. [^1]) for citations.\nEnsure citation formatting of the summary uses markdown footnotes and consistent with the source material.\nNo footnotes in titles. Do not include a heading for references, just include footnotes."}],"timestamp":"2026-03-12T20:06:01.503712","runnable_id":"b0cf41c5-0708-45d1-b450-846f2bc97202"},"review":{"id":"7aba2bff-cbaa-4fd1-8391-b80f10b9a8e6","key":"review","value":"Overall this is a useful, well‑synthesised draft, but it needs tightening to avoid small attribution and overgeneralisation errors. Concise points and a corrected one‑paragraph summary follow.\n\nMain problems to fix\n- Citation placement: some claims mix cell types and citations (e.g., KLF4–p62/ endothelial autophagy is supported by [^4], not [^2]; [^2] is proximal‑tubule TGF‑β work). Separate citations by the specific cell/type claim.  \n- Tone/strength: several sentences imply clinical validation or broad preservation of renal function without always specifying preclinical/cellular evidence. Add qualifiers (e.g., \"preclinical/cell/animal data show…\") where appropriate.  \n- Specificity: state which findings are epigenetic, autophagic, inflammatory or ferroptotic and cite accordingly rather than grouping loosely.  \n- Minor wording: use consistent terminology (e.g., ferroptosis rather than only the informal “iron death”), and avoid implying causality in human disease beyond what the patient‑level studies show.\n\nRevised concise summary (citations corrected and phrasing tightened)\nMultiple cellular, animal and patient‑level studies indicate KLF4 is downregulated in diabetic kidney disease, and preclinical data show restoring KLF4 can preserve podocyte, tubular and endothelial phenotypes through complementary mechanisms. In podocytes KLF4 maintains epithelial identity and nephrin expression via epigenetic (DNA‑methylation) remodeling and loss of KLF4 worsens proteinuria; KLF4 overexpression reduces albuminuria and podocyte apoptosis and activates autophagy via inhibition of the mTOR/S6K axis[^1][^3]. In proximal tubule cells KLF4 dampens TGF‑β1–driven inflammatory mediators (MIF, MCP‑1), while effects on extracellular matrix proteins are less clear[^2]. A KLF4–p62 axis has been implicated in protecting vascular endothelial cells via mTOR‑dependent autophagy[^4]. Bioinformatic analyses implicate ferroptosis pathways in diabetic nephropathy, and patient studies report altered KLF4 expression and promoter methylation in diabetes; experimental work shows berberine reduces KLF4 promoter methylation and ferroptosis and improves renal outcomes in mice[^5][^7][^6]. Smaller interventional studies (e.g., THC in diabetic rats) and reviews emphasizing mitochondrial/mitophagy dysfunction further place KLF4 at the intersection of epigenetic, autophagic and redox/ferroptotic pathways relevant to DKD, supporting further validation in human studies[^8][^9].\n\nConcise actionable edits you can apply to the original paragraph\n- Move the [^4] citation to the clause about endothelial KLF4–p62 and leave [^2] for proximal tubule claims.  \n- Precede broad claims about \"preserving renal function\" with “preclinical data show” (or similar).  \n- Replace informal phrase “iron death” with “ferroptosis” (or write both once: ferroptosis (“iron death”)).  \n- If you state “links KLF4 to ferroptosis” ensure that the bioinformatic source explicitly reports KLF4 (otherwise phrase as “ferroptosis pathways implicated in DN and KLF4 methylation/expression altered in patients”).","timestamp":"2026-03-12T20:05:25.48199","runnable_id":"b0cf41c5-0708-45d1-b450-846f2bc97202"},"deepdive_v1":{"id":"7206f645-2c55-4e8e-95c2-515b585b6404","key":"deepdive_v1","value":{"input":"KLF4 & Diabetic Nephropathy"},"timestamp":"2026-03-12T20:04:58.61445","runnable_id":"b0cf41c5-0708-45d1-b450-846f2bc97202"},"deepdive_v1.input":{"id":"6ac10415-ac92-4b35-9bd0-5e969e234846","key":"deepdive_v1.input","value":"KLF4 & Diabetic Nephropathy","timestamp":"2026-03-12T20:04:58.616219","runnable_id":"b0cf41c5-0708-45d1-b450-846f2bc97202"},"deepdive_v1.output":{"id":"8eab4eee-6467-4a05-be4c-4aa73c0bace7","key":"deepdive_v1.output","value":"# KLF4 in diabetic nephropathy: roles, mechanisms and therapeutic leads\n\nCollectively, studies across cellular, animal and human samples indicate that KLF4 is downregulated in diabetic kidney disease and that restoring KLF4 activity preserves glomerular and tubular function through multiple mechanisms: in podocytes KLF4 maintains epithelial identity and nephrin expression via epigenetic (DNA methylation) remodeling and its loss worsens proteinuria, while KLF4 overexpression reduces albuminuria and podocyte apoptosis and activates autophagy by inhibiting the mTOR/S6K axis[^1][^3]. In proximal tubule cells KLF4 dampens TGF‑β1–driven inflammatory responses (MIF, MCP‑1) though effects on extracellular matrix proteins were less clear, and a KLF4–p62 axis has been implicated in protecting endothelial cells via mTOR‑dependent autophagy[^2][^4]. Bioinformatic and patient‑level studies additionally link KLF4 to regulated cell‑death programs relevant to diabetic nephropathy (ferroptosis/“iron death”) and report altered KLF4 expression and promoter methylation in diabetes, supporting translational approaches that target KLF4 epigenetic regulation (e.g., berberine reduces KLF4 promoter methylation and ferroptosis and improves renal outcomes in mice) as well as pharmacologic/biologic modulation in preclinical models[^5][^7][^6]. Smaller interventional studies (e.g., THC) and reviews emphasizing mitochondrial/mitophagy dysfunction further suggest KLF4 sits at the intersection of epigenetic, autophagic and redox/ferroptotic pathways relevant to DKD, making it a promising mechanistic and therapeutic target that warrants further human validation[^8][^9].\n\n[^1]: Hayashi K, Sasamura H, Nakamura M, et al. KLF4‑dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. J Clin Invest. 2014. doi:10.1172/JCI69557  \n[^2]: Mreich E, Chen X‑M, Zaky A, et al. The role of Krüppel‑like factor 4 in transforming growth factor‑β‑induced inflammatory and fibrotic responses in human proximal tubule cells. Clin Exp Pharmacol Physiol. 2015. doi:10.1111/1440‑1681.12405  \n[^3]: Gong J, Zhan H, Li Y, et al. Krüppel‑like factor 4 ameliorates diabetic kidney disease by activating autophagy via the mTOR pathway. Mol Med Rep. 2019. doi:10.3892/mmr.2019.10585  \n[^4]: Wang X, Su W, Ma M, et al. The KLF4‑p62 axis prevents vascular endothelial cell injury via the mTOR/S6K pathway and autophagy in diabetic kidney disease. Endokrynol Pol. 2022. doi:10.5603/EP.a2022.0072  \n[^5]: Hu Y, Liu S, Liu W, et al. Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches. PLoS One. 2021. doi:10.1371/journal.pone.0259436  \n[^6]: Cai S, Zhu H, Chen L, et al. Berberine Inhibits KLF4 Promoter Methylation and Ferroptosis to Ameliorate Diabetic Nephropathy in Mice. Chem Res Toxicol. 2024. doi:10.1021/acs.chemrestox.4c00263  \n[^7]: Coskun ZM, Ersoz M, Adas M, et al. Kruppel‑Like Transcription Factor‑4 Gene Expression and DNA Methylation Status in Type 2 Diabetes and Diabetic Nephropathy Patients. Arch Med Res. 2019. doi:10.1016/j.arcmed.2019.05.012  \n[^8]: Yanar K, Coskun ZM, Beydogan AB, et al. The effects of delta‑9‑tetrahydrocannabinol on Krüppel‑like factor‑4 expression, redox homeostasis, and inflammation in the kidney of diabetic rat. J Cell Biochem. 2019. doi:10.1002/jcb.28903  \n[^9]: Pavlović N, Križanac M, Kumrić M, et al. Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression. Cells. 2025. doi:10.3390/cells14110794","timestamp":"2026-03-12T20:05:25.478875","runnable_id":"b0cf41c5-0708-45d1-b450-846f2bc97202"},"deepdive_v1.prompt":{"id":"d0a524aa-679d-4f12-80c9-acba9413d692","key":"deepdive_v1.prompt","value":[{"role":"user","content":"Search: KLF4 & Diabetic Nephropathy"},{"role":"user","content":"Results: ## Source Material\nHere are the abstracts of the top highly cited studies relevant to the search.\n\n### KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria.\n\nThe transcription factor Kruppel-like factor 4 (KLF4) has the ability, along with other factors, to reprogram somatic cells into induced pluripotent stem (iPS) cells. Here, we determined that KLF4 is expressed in kidney glomerular podocytes and is decreased in both animal models and humans exhibiting a proteinuric. Transient restoration of KLF4 expression in podocytes of diseased glomeruli in vivo, either by gene transfer or transgenic expression, resulted in a sustained increase in nephrin expression and a decrease in albuminuria. In mice harboring podocyte-specific deletion of Klf4, adriamycin-induced proteinuria was substantially exacerbated, although these animals displayed minimal phenotypical changes prior to adriamycin administration. KLF4 overexpression in cultured human podocytes increased expression of nephrin and other epithelial markers and reduced mesenchymal gene expression. DNA methylation profiling and bisulfite genomic sequencing revealed that KLF4 expression reduced methylation at the nephrin promoter and the promoters of other epithelial markers; however, methylation was increased at the promoters of genes encoding mesenchymal markers, suggesting selective epigenetic regulation of podocyte gene expression. Together, these results suggest that KLF4 epigenetically modulates podocyte phenotype and function and that the podocyte epigenome can be targeted for direct intervention and reduction of proteinuria.\n\nCited by: 102  \nCite this article: Hayashi, Kaori., Sasamura, Hiroyuki., Nakamura, Mari., et al. **KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria.** *J Clin Invest (2014)*. doi:10.1172/JCI69557\n\n### Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches.\n\nDiabetic nephropathy is one of the common microvascular complications of diabetes. Iron death is a recently reported way of cell death. To explore the effects of iron death on diabetic nephropathy, iron death score of diabetic nephropathy was analyzed based on the network and pathway levels. Furthermore, markers related to iron death were screened. Using RNA-seq data of diabetic nephropathy, samples were clustered uniformly and the disease was classified. Differentially expressed gene analysis was conducted on the typed disease samples, and the WGCNA algorithm was used to obtain key modules. String database was used to perform protein interaction analysis on key module genes for the selection of Hub genes. Moreover, principal component analysis method was applied to get transcription factors and non-coding genes, which interact with the Hub gene. All samples can be divided into two categories and principal component analysis shows that the two categories are significantly different. Hub genes (FPR3, C3AR1, CD14, ITGB2, RAC2 and ITGAM) related to iron death in diabetic nephropathy were obtained through gene expression differential analysis between different subtypes. Non-coding genes that interact with Hub genes, including hsa-miR-572, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-208a-3p, hsa-miR-153-3p and hsa-miR-29c-3p, may be related to diabetic nephropathy. Transcription factors HIF1α, KLF4, KLF5, RUNX1, SP1, VDR and WT1 may be related to diabetic nephropathy. The above factors and Hub genes are collectively involved in the occurrence and development of diabetic nephropathy, which can be further studied in the future. Moreover, these factors and genes may be potential target for therapeutic drugs.\n\nCited by: 31  \nCite this article: Hu, Yaling., Liu, Shuang., Liu, Wenyuan., et al. **Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches.** *PLoS One (2021)*. doi:10.1371/journal.pone.0259436\n\n### The role of Krüppel-like factor 4 in transforming growth factor-β-induced inflammatory and fibrotic responses in human proximal tubule cells.\n\nKrüppel-like factor 4 (KLF4) is known to mitigate inflammation in several cell types. Using human proximal tubule cells, the present study aimed to investigate the role of KLF4 in regulating transforming growth factor (TGF)-β₁ induced inflammatory and fibrotic responses. Human kidney proximal tubular cells were exposed to high glucose, or TGF-β₁ and KLF4 expressions were determined. Cells were then transfected with empty vector or KLF4 and exposed to 2-ng/mL TGF-β₁ for up to 72 h. Inflammatory proteins (macrophage migration inhibitory factor and monocyte chemoattractant protein-1) and pro-fibrotic proteins (fibronectin and collagen IV) were measured after 72 h by enzyme-linked immunosorbent assay and western blot, respectively. To determine the relevance to in vivo models of chronic kidney disease, KLF4 protein expression in streptozotocin-induced diabetic mice was determined. Krüppel-like factor 4 messenger RNA (mRNA) levels were significantly reduced in high glucose-treated human kidney proximal tubular cells. High glucose increased TGF-β₁ mRNA expression, which significantly increased migration inhibitory factor and monocyte chemoattractant protein-1 protein secretion. Transforming growth factor-β₁ significantly increased fibronectin and collagen IV protein expression. The overexpression of KLF4 significantly reduced TGF-β-mediated increases in migration inhibitory factor and monocyte chemoattractant protein-1 but had no effect on TGF-β-mediated fibronectin and collagen IV mRNA and protein expression. The levels of KLF4 mRNA were significantly reduced in the diabetic kidney, and diabetic animals had a significant reduction in renal tubular expression of KLF4 proteins. This data suggest that KLF4 reduces inflammation induced by TGF-β₁, suggesting a therapeutic role for KLF4 in diabetic nephropathy.\n\nCited by: 23  \nCite this article: Mreich, Ellein., Chen, Xin-Ming., Zaky, Amgad., et al. **The role of Krüppel-like factor 4 in transforming growth factor-β-induced inflammatory and fibrotic responses in human proximal tubule cells.** *Clin Exp Pharmacol Physiol (2015)*. doi:10.1111/1440-1681.12405\n\n### Krüppel‑like factor 4 ameliorates diabetic kidney disease by activating autophagy via the mTOR pathway.\n\nDiabetic kidney disease (DKD) is diagnosed increasingly frequently and represents a serious threat to human health. Krüppel‑like factor 4 (KLF4) has aroused attention due to its potential effect on podocytes and in ameliorating proteinuria associated with glomerulopathy. The purpose of the present study was to investigate the potential role of KLF4 in DKD. It was hypothesized that KLF4 impacts diabetic nephropathy by mediating the podocyte autophagic process. A KLF4 plasmid vector was constructed, and podocytes were transfected and incubated with DKD mice serum for in vitro experiments. A db/db spontaneous DKD mouse model was also established for in vivo study. After treatment, the level of serum creatinine (Scr), blood urea nitrogen (BUN), and 24‑h urinary protein was determined. Immunofluorescence and periodic acid‑Schiff staining, western blotting, flow cytometry and a TUNEL assay were performed to observe changes in glomerular morphology and the level of apoptosis, cytoskeleton proteins, epithelial‑mesenchymal transition (EMT) biomarkers, autophagic proteins and mTOR pathway proteins in each group. KLF4 overexpression significantly reduced the level of urinary albumin, Scr, BUN and attenuated mesangial matrix expansion, as well as mesangial cell proliferation in DKD mice. KLF4 overexpression also inhibited podocyte apoptosis and downregulated vimentin and α‑smooth muscle actin, and upregulated E‑cadherin and nephrin, both in vivo and in vitro. Moreover, the microtubule associated protein 1 light chain 3α (LC3)‑II/LC3‑I ratio and LC3‑II fluorescence was significantly increased in the vector‑KLF4 group compared to the negative control vector group both in vivo and in vitro. Finally, a decrease in the level of phosphorylated (p)‑mTOR and p‑S6K protein expression was observed following KLF4 overexpression in vitro. The present findings suggested that KLF4 plays a renoprotective role in DKD, which is associated with the activation of podocyte autophagy, and may be involved in the mTOR signaling pathway.\n\nCited by: 21  \nCite this article: Gong, Jianguang., Zhan, Huifang., Li, Yiwen., et al. **Krüppel‑like factor 4 ameliorates diabetic kidney disease by activating autophagy via the mTOR pathway.** *Mol Med Rep (2019)*. doi:10.3892/mmr.2019.10585\n\n### Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression.\n\nMitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia-reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as  PMPCB  and  TFAM . Epigenetic dysregulation also impacts mitochondrial-ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions-ranging from Drp1 inhibition to mitochondrial transplantation-hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies.\n\nCited by: 20  \nCite this article: Pavlović, Nikola., Križanac, Marinela., Kumrić, Marko., et al. **Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression.** *Cells (2025)*. doi:10.3390/cells14110794\n\n### The KLF4-p62 axis prevents vascular endothelial cell injury via the mTOR/S6K pathway and autophagy in diabetic kidney disease.\n\nDiabetic kidney disease (DKD) is a complication of systemic diabetic microangiopathy, which has a high risk of developing into end-stage renal disease and death. This study explored the mechanism underlying autophagy in DKD vascular endothelial cell injury.\n\nCited by: 13  \nCite this article: Wang, Xinxing., Su, Wei., Ma, Mingze., et al. **The KLF4-p62 axis prevents vascular endothelial cell injury via the mTOR/S6K pathway and autophagy in diabetic kidney disease.** *Endokrynol Pol (2022)*. doi:10.5603/EP.a2022.0072\n\n### Berberine Inhibits KLF4 Promoter Methylation and Ferroptosis to Ameliorate Diabetic Nephropathy in Mice.\n\nInflammation, oxidative stress, fibrosis, and ferroptosis play important roles in diabetic nephropathy development. Krüppel-like factor 4 (KLF4) is a transcriptional factor, which regulates multiple cell processes and is involved in diabetic nephropathy. Berberine has various biological activities, including anti-inflammation, antioxidative stress, and antiferroptosis. Berberine has been shown to inhibit diabetic nephropathy, but whether it involves KLF4 and ferroptosis remains unknown. We established a diabetic nephropathy mice model and administered berberine to the mice. The kidney function, renal structure and fibrosis, expression of KLF4 and DNA methylation enzymes, DNA methylation of the KLF4 promoter, mitochondria structure, and expression of oxidative stress and ferroptosis markers were analyzed. Berberine rescued kidney function and renal structure and prevented renal fibrosis in diabetic nephropathy mice. Berberine suppressed the expression of DNMT1 and DNMT2 and upregulated KLF4 expression by preventing KLF4 promoter methylation. Berberine inhibited the expression of oxidative stress and ferroptosis markers, maintained mitochondria structure, and prevented ferroptosis. Berberine ameliorates diabetic nephropathy by inhibiting Klf4 promoter methylation and ferroptosis.\n\nCited by: 12  \nCite this article: Cai, Shengyu., Zhu, Huizheng., Chen, Lingling., et al. **Berberine Inhibits KLF4 Promoter Methylation and Ferroptosis to Ameliorate Diabetic Nephropathy in Mice.** *Chem Res Toxicol (2024)*. doi:10.1021/acs.chemrestox.4c00263\n\n### Kruppel-Like Transcription Factor-4 Gene Expression and DNA Methylation Status in Type 2 Diabetes and Diabetic Nephropathy Patients.\n\nDiabetic nephropathy (DN) is one of the most serious microvascular complications in diabetic patients. The kruppel-like transcription factor-4 (KLF-4) affects the expression of genes involved in the pathogenesis of DN. The present study aims to identify the KLF-4 expression and DNA methylation (DNAMe) status in patients with type-2 diabetes (T2D) and DN and to reveal the contribution of the KLF-4 to the development of DN.\n\nCited by: 9  \nCite this article: Coskun, Zeynep Mine., Ersoz, Melike., Adas, Mine., et al. **Kruppel-Like Transcription Factor-4 Gene Expression and DNA Methylation Status in Type 2 Diabetes and Diabetic Nephropathy Patients.** *Arch Med Res (2019)*. doi:10.1016/j.arcmed.2019.05.012\n\n### A clinical and in-silico study of microRNA-21 and growth differentiation factor-15 expression in pre-diabetes, type 2 diabetes and diabetic nephropathy.\n\nDiabetic nephropathy (DN), a microvascular complication associated with long-standing diabetes, is a major cause of the end-stage renal disease (ESRD). Our in-silico analysis indicates several enrichment analyses involved in glucose metabolism to be affected by GDF15 transcription factors.\n\nCited by: 4  \nCite this article: Agarwal, Riddhi G., Khokhar, Manoj., Purohit, Purvi., et al. **A clinical and in-silico study of microRNA-21 and growth differentiation factor-15 expression in pre-diabetes, type 2 diabetes and diabetic nephropathy.** *Minerva Endocrinol (Torino) (2023)*. doi:10.23736/S2724-6507.22.03646-6\n\n### The effects of delta-9-tetrahydrocannabinol on Krüppel-like factor-4 expression, redox homeostasis, and inflammation in the kidney of diabetic rat.\n\nDiabetes mellitus is a complex, multifactorial disorder that is attributed to pancreatic β cell dysfunction. Pancreatic β cell dysfunction results in declining utilization of glucose by peripheral tissues as kidney and it leads to nephropathy. Excessive production and accumulation of free radicals and incapable antioxidant defense system lead to impaired redox status. Macromolecular damage may occur due to impaired redox status and also immune imbalance. Δ9-Tetrahydrocannabinol (THC) is the main active ingredient in cannabis. THC acts as an immunomodulator and an antioxidant agent. Our aim was to evaluate the effects of THC in the diabetic kidney. We analyzed macromolecular damage biomarkers as protein carbonyl (PCO), lipid hydroperoxide (LHP), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and antioxidant defense system biomarkers as thiol fractions (T-SH, NP-SH, P-SH) and Cu/Zn-superoxide dismutase activity for the antioxidative effects of THC. Furthermore, mRNA expression of Krüppel-like factor-4, secreted immunopositive cell number changes of interleukin-6, nuclear factor κβ (NF-κβ), and peroxisome proliferator-activated receptor-γ and tumor necrosis factor α (TNF-α) levels were analyzed for the immunomodulatory activity of THC. Diabetic rats showed significantly increased levels of PCO, LHP, MDA, and 8-OHdG when compared with controls (P < 0.05 for each parameter). THC significantly reduced the elevated levels of PCO and 8-OHdG (P < 0.05 for both parameters) and also LHP and MDA levels were insignificantly reduced by THC. Also, thiol fractions insignificantly increased in THC administered diabetic kidney when compared with diabetic rats. The NF-κβ cell number significantly decreased in the diabetic rats treated with THC compared with the diabetic group. According to our data, THC has ameliorative effects on the impaired redox status of diabetic kidney and also it acts as an immunomodulator. Therefore, THC might be used as a therapeutic agent for diabetic kidneys but its usage in the healthy kidney may show adverse effects.\n\nCited by: 3  \nCite this article: Yanar, Karolin., Coskun, Zeynep Mine., Beydogan, Alisa Bahar., et al. **The effects of delta-9-tetrahydrocannabinol on Krüppel-like factor-4 expression, redox homeostasis, and inflammation in the kidney of diabetic rat.** *J Cell Biochem (2019)*. doi:10.1002/jcb.28903"},{"role":"user","content":"Write a paragraph summary for a biologist that summarizes what the studies say about the search.\nOutput in markdown, start with an informative title, use footnote formatting (e.g. [^1]) for citations.\nEnsure citation formatting of the summary uses markdown footnotes and consistent with the source material.\nNo footnotes in titles. Do not include a heading for references, just include footnotes."}],"timestamp":"2026-03-12T20:04:59.107254","runnable_id":"b0cf41c5-0708-45d1-b450-846f2bc97202"},"deepdive_v1.ncbi_search":{"id":"26d1fb06-958c-427a-ae1e-6b90b0546461","key":"deepdive_v1.ncbi_search","value":"## Source Material\nHere are the abstracts of the top highly cited studies relevant to the search.\n\n### KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria.\n\nThe transcription factor Kruppel-like factor 4 (KLF4) has the ability, along with other factors, to reprogram somatic cells into induced pluripotent stem (iPS) cells. Here, we determined that KLF4 is expressed in kidney glomerular podocytes and is decreased in both animal models and humans exhibiting a proteinuric. Transient restoration of KLF4 expression in podocytes of diseased glomeruli in vivo, either by gene transfer or transgenic expression, resulted in a sustained increase in nephrin expression and a decrease in albuminuria. In mice harboring podocyte-specific deletion of Klf4, adriamycin-induced proteinuria was substantially exacerbated, although these animals displayed minimal phenotypical changes prior to adriamycin administration. KLF4 overexpression in cultured human podocytes increased expression of nephrin and other epithelial markers and reduced mesenchymal gene expression. DNA methylation profiling and bisulfite genomic sequencing revealed that KLF4 expression reduced methylation at the nephrin promoter and the promoters of other epithelial markers; however, methylation was increased at the promoters of genes encoding mesenchymal markers, suggesting selective epigenetic regulation of podocyte gene expression. Together, these results suggest that KLF4 epigenetically modulates podocyte phenotype and function and that the podocyte epigenome can be targeted for direct intervention and reduction of proteinuria.\n\nCited by: 102  \nCite this article: Hayashi, Kaori., Sasamura, Hiroyuki., Nakamura, Mari., et al. **KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria.** *J Clin Invest (2014)*. doi:10.1172/JCI69557\n\n### Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches.\n\nDiabetic nephropathy is one of the common microvascular complications of diabetes. Iron death is a recently reported way of cell death. To explore the effects of iron death on diabetic nephropathy, iron death score of diabetic nephropathy was analyzed based on the network and pathway levels. Furthermore, markers related to iron death were screened. Using RNA-seq data of diabetic nephropathy, samples were clustered uniformly and the disease was classified. Differentially expressed gene analysis was conducted on the typed disease samples, and the WGCNA algorithm was used to obtain key modules. String database was used to perform protein interaction analysis on key module genes for the selection of Hub genes. Moreover, principal component analysis method was applied to get transcription factors and non-coding genes, which interact with the Hub gene. All samples can be divided into two categories and principal component analysis shows that the two categories are significantly different. Hub genes (FPR3, C3AR1, CD14, ITGB2, RAC2 and ITGAM) related to iron death in diabetic nephropathy were obtained through gene expression differential analysis between different subtypes. Non-coding genes that interact with Hub genes, including hsa-miR-572, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-208a-3p, hsa-miR-153-3p and hsa-miR-29c-3p, may be related to diabetic nephropathy. Transcription factors HIF1α, KLF4, KLF5, RUNX1, SP1, VDR and WT1 may be related to diabetic nephropathy. The above factors and Hub genes are collectively involved in the occurrence and development of diabetic nephropathy, which can be further studied in the future. Moreover, these factors and genes may be potential target for therapeutic drugs.\n\nCited by: 31  \nCite this article: Hu, Yaling., Liu, Shuang., Liu, Wenyuan., et al. **Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches.** *PLoS One (2021)*. doi:10.1371/journal.pone.0259436\n\n### The role of Krüppel-like factor 4 in transforming growth factor-β-induced inflammatory and fibrotic responses in human proximal tubule cells.\n\nKrüppel-like factor 4 (KLF4) is known to mitigate inflammation in several cell types. Using human proximal tubule cells, the present study aimed to investigate the role of KLF4 in regulating transforming growth factor (TGF)-β₁ induced inflammatory and fibrotic responses. Human kidney proximal tubular cells were exposed to high glucose, or TGF-β₁ and KLF4 expressions were determined. Cells were then transfected with empty vector or KLF4 and exposed to 2-ng/mL TGF-β₁ for up to 72 h. Inflammatory proteins (macrophage migration inhibitory factor and monocyte chemoattractant protein-1) and pro-fibrotic proteins (fibronectin and collagen IV) were measured after 72 h by enzyme-linked immunosorbent assay and western blot, respectively. To determine the relevance to in vivo models of chronic kidney disease, KLF4 protein expression in streptozotocin-induced diabetic mice was determined. Krüppel-like factor 4 messenger RNA (mRNA) levels were significantly reduced in high glucose-treated human kidney proximal tubular cells. High glucose increased TGF-β₁ mRNA expression, which significantly increased migration inhibitory factor and monocyte chemoattractant protein-1 protein secretion. Transforming growth factor-β₁ significantly increased fibronectin and collagen IV protein expression. The overexpression of KLF4 significantly reduced TGF-β-mediated increases in migration inhibitory factor and monocyte chemoattractant protein-1 but had no effect on TGF-β-mediated fibronectin and collagen IV mRNA and protein expression. The levels of KLF4 mRNA were significantly reduced in the diabetic kidney, and diabetic animals had a significant reduction in renal tubular expression of KLF4 proteins. This data suggest that KLF4 reduces inflammation induced by TGF-β₁, suggesting a therapeutic role for KLF4 in diabetic nephropathy.\n\nCited by: 23  \nCite this article: Mreich, Ellein., Chen, Xin-Ming., Zaky, Amgad., et al. **The role of Krüppel-like factor 4 in transforming growth factor-β-induced inflammatory and fibrotic responses in human proximal tubule cells.** *Clin Exp Pharmacol Physiol (2015)*. doi:10.1111/1440-1681.12405\n\n### Krüppel‑like factor 4 ameliorates diabetic kidney disease by activating autophagy via the mTOR pathway.\n\nDiabetic kidney disease (DKD) is diagnosed increasingly frequently and represents a serious threat to human health. Krüppel‑like factor 4 (KLF4) has aroused attention due to its potential effect on podocytes and in ameliorating proteinuria associated with glomerulopathy. The purpose of the present study was to investigate the potential role of KLF4 in DKD. It was hypothesized that KLF4 impacts diabetic nephropathy by mediating the podocyte autophagic process. A KLF4 plasmid vector was constructed, and podocytes were transfected and incubated with DKD mice serum for in vitro experiments. A db/db spontaneous DKD mouse model was also established for in vivo study. After treatment, the level of serum creatinine (Scr), blood urea nitrogen (BUN), and 24‑h urinary protein was determined. Immunofluorescence and periodic acid‑Schiff staining, western blotting, flow cytometry and a TUNEL assay were performed to observe changes in glomerular morphology and the level of apoptosis, cytoskeleton proteins, epithelial‑mesenchymal transition (EMT) biomarkers, autophagic proteins and mTOR pathway proteins in each group. KLF4 overexpression significantly reduced the level of urinary albumin, Scr, BUN and attenuated mesangial matrix expansion, as well as mesangial cell proliferation in DKD mice. KLF4 overexpression also inhibited podocyte apoptosis and downregulated vimentin and α‑smooth muscle actin, and upregulated E‑cadherin and nephrin, both in vivo and in vitro. Moreover, the microtubule associated protein 1 light chain 3α (LC3)‑II/LC3‑I ratio and LC3‑II fluorescence was significantly increased in the vector‑KLF4 group compared to the negative control vector group both in vivo and in vitro. Finally, a decrease in the level of phosphorylated (p)‑mTOR and p‑S6K protein expression was observed following KLF4 overexpression in vitro. The present findings suggested that KLF4 plays a renoprotective role in DKD, which is associated with the activation of podocyte autophagy, and may be involved in the mTOR signaling pathway.\n\nCited by: 21  \nCite this article: Gong, Jianguang., Zhan, Huifang., Li, Yiwen., et al. **Krüppel‑like factor 4 ameliorates diabetic kidney disease by activating autophagy via the mTOR pathway.** *Mol Med Rep (2019)*. doi:10.3892/mmr.2019.10585\n\n### Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression.\n\nMitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia-reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as  PMPCB  and  TFAM . Epigenetic dysregulation also impacts mitochondrial-ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions-ranging from Drp1 inhibition to mitochondrial transplantation-hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies.\n\nCited by: 20  \nCite this article: Pavlović, Nikola., Križanac, Marinela., Kumrić, Marko., et al. **Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression.** *Cells (2025)*. doi:10.3390/cells14110794\n\n### The KLF4-p62 axis prevents vascular endothelial cell injury via the mTOR/S6K pathway and autophagy in diabetic kidney disease.\n\nDiabetic kidney disease (DKD) is a complication of systemic diabetic microangiopathy, which has a high risk of developing into end-stage renal disease and death. This study explored the mechanism underlying autophagy in DKD vascular endothelial cell injury.\n\nCited by: 13  \nCite this article: Wang, Xinxing., Su, Wei., Ma, Mingze., et al. **The KLF4-p62 axis prevents vascular endothelial cell injury via the mTOR/S6K pathway and autophagy in diabetic kidney disease.** *Endokrynol Pol (2022)*. doi:10.5603/EP.a2022.0072\n\n### Berberine Inhibits KLF4 Promoter Methylation and Ferroptosis to Ameliorate Diabetic Nephropathy in Mice.\n\nInflammation, oxidative stress, fibrosis, and ferroptosis play important roles in diabetic nephropathy development. Krüppel-like factor 4 (KLF4) is a transcriptional factor, which regulates multiple cell processes and is involved in diabetic nephropathy. Berberine has various biological activities, including anti-inflammation, antioxidative stress, and antiferroptosis. Berberine has been shown to inhibit diabetic nephropathy, but whether it involves KLF4 and ferroptosis remains unknown. We established a diabetic nephropathy mice model and administered berberine to the mice. The kidney function, renal structure and fibrosis, expression of KLF4 and DNA methylation enzymes, DNA methylation of the KLF4 promoter, mitochondria structure, and expression of oxidative stress and ferroptosis markers were analyzed. Berberine rescued kidney function and renal structure and prevented renal fibrosis in diabetic nephropathy mice. Berberine suppressed the expression of DNMT1 and DNMT2 and upregulated KLF4 expression by preventing KLF4 promoter methylation. Berberine inhibited the expression of oxidative stress and ferroptosis markers, maintained mitochondria structure, and prevented ferroptosis. Berberine ameliorates diabetic nephropathy by inhibiting Klf4 promoter methylation and ferroptosis.\n\nCited by: 12  \nCite this article: Cai, Shengyu., Zhu, Huizheng., Chen, Lingling., et al. **Berberine Inhibits KLF4 Promoter Methylation and Ferroptosis to Ameliorate Diabetic Nephropathy in Mice.** *Chem Res Toxicol (2024)*. doi:10.1021/acs.chemrestox.4c00263\n\n### Kruppel-Like Transcription Factor-4 Gene Expression and DNA Methylation Status in Type 2 Diabetes and Diabetic Nephropathy Patients.\n\nDiabetic nephropathy (DN) is one of the most serious microvascular complications in diabetic patients. The kruppel-like transcription factor-4 (KLF-4) affects the expression of genes involved in the pathogenesis of DN. The present study aims to identify the KLF-4 expression and DNA methylation (DNAMe) status in patients with type-2 diabetes (T2D) and DN and to reveal the contribution of the KLF-4 to the development of DN.\n\nCited by: 9  \nCite this article: Coskun, Zeynep Mine., Ersoz, Melike., Adas, Mine., et al. **Kruppel-Like Transcription Factor-4 Gene Expression and DNA Methylation Status in Type 2 Diabetes and Diabetic Nephropathy Patients.** *Arch Med Res (2019)*. doi:10.1016/j.arcmed.2019.05.012\n\n### A clinical and in-silico study of microRNA-21 and growth differentiation factor-15 expression in pre-diabetes, type 2 diabetes and diabetic nephropathy.\n\nDiabetic nephropathy (DN), a microvascular complication associated with long-standing diabetes, is a major cause of the end-stage renal disease (ESRD). Our in-silico analysis indicates several enrichment analyses involved in glucose metabolism to be affected by GDF15 transcription factors.\n\nCited by: 4  \nCite this article: Agarwal, Riddhi G., Khokhar, Manoj., Purohit, Purvi., et al. **A clinical and in-silico study of microRNA-21 and growth differentiation factor-15 expression in pre-diabetes, type 2 diabetes and diabetic nephropathy.** *Minerva Endocrinol (Torino) (2023)*. doi:10.23736/S2724-6507.22.03646-6\n\n### The effects of delta-9-tetrahydrocannabinol on Krüppel-like factor-4 expression, redox homeostasis, and inflammation in the kidney of diabetic rat.\n\nDiabetes mellitus is a complex, multifactorial disorder that is attributed to pancreatic β cell dysfunction. Pancreatic β cell dysfunction results in declining utilization of glucose by peripheral tissues as kidney and it leads to nephropathy. Excessive production and accumulation of free radicals and incapable antioxidant defense system lead to impaired redox status. Macromolecular damage may occur due to impaired redox status and also immune imbalance. Δ9-Tetrahydrocannabinol (THC) is the main active ingredient in cannabis. THC acts as an immunomodulator and an antioxidant agent. Our aim was to evaluate the effects of THC in the diabetic kidney. We analyzed macromolecular damage biomarkers as protein carbonyl (PCO), lipid hydroperoxide (LHP), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and antioxidant defense system biomarkers as thiol fractions (T-SH, NP-SH, P-SH) and Cu/Zn-superoxide dismutase activity for the antioxidative effects of THC. Furthermore, mRNA expression of Krüppel-like factor-4, secreted immunopositive cell number changes of interleukin-6, nuclear factor κβ (NF-κβ), and peroxisome proliferator-activated receptor-γ and tumor necrosis factor α (TNF-α) levels were analyzed for the immunomodulatory activity of THC. Diabetic rats showed significantly increased levels of PCO, LHP, MDA, and 8-OHdG when compared with controls (P < 0.05 for each parameter). THC significantly reduced the elevated levels of PCO and 8-OHdG (P < 0.05 for both parameters) and also LHP and MDA levels were insignificantly reduced by THC. Also, thiol fractions insignificantly increased in THC administered diabetic kidney when compared with diabetic rats. The NF-κβ cell number significantly decreased in the diabetic rats treated with THC compared with the diabetic group. According to our data, THC has ameliorative effects on the impaired redox status of diabetic kidney and also it acts as an immunomodulator. Therefore, THC might be used as a therapeutic agent for diabetic kidneys but its usage in the healthy kidney may show adverse effects.\n\nCited by: 3  \nCite this article: Yanar, Karolin., Coskun, Zeynep Mine., Beydogan, Alisa Bahar., et al. **The effects of delta-9-tetrahydrocannabinol on Krüppel-like factor-4 expression, redox homeostasis, and inflammation in the kidney of diabetic rat.** *J Cell Biochem (2019)*. doi:10.1002/jcb.28903","timestamp":"2026-03-12T20:04:59.103038","runnable_id":"b0cf41c5-0708-45d1-b450-846f2bc97202"}},"num_comments":"0"}}}]