Podocyte-Specific Induction of Krüppel-Like Factor 15 Restores Differentiation Markers and Attenuates Kidney Injury in Proteinuric Kidney Disease

Guo, Yiqing; Pace, Jesse; Li, Zhengzhe; Ma’ayan, Avi; Wang, Zichen; Revelo, Mônica P.; Chen, Edward; Gu, Xiangchen; Attalah, Ahmed; Yang, Yaqi; Estrada, Chelsea; Yang, Vincent W.; He, John Cijiang; Mallipattu, Sandeep K.

doi:10.1681/asn.2018030324

Cited by 32 publications

(27 citation statements)

References 75 publications

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“…These findings suggest that the compound rescues the filtration and endocytic functions mediated by the Cubn/ Amnionless complex, which were decreased in IR-Rph flies. This restoration could be due to the upregulation of Klf15, which controls sns expression, as proven in previous studies (Mallipattu et al, 2012;Guo et al, 2018). Additionally, as shown in the TEM images, the nephrocytes of RA-treated flies recovered the labyrinthine channel structures (Fig.…”

Section: Disease Models and Mechanismssupporting

confidence: 81%

“…It is involved in different processes such as cellular differentiation, proliferation, apoptosis regulation and inflammation inhibition ( Niederreither and Dollé, 2008 ). It is known that RA also plays a role in podocyte differentiation via KLF15 regulation ( Mallipattu et al, 2012 ; Niederreither and Dollé, 2008 ; Guo et al, 2018 ; Mallipattu and He, 2015 ; Sharma et al, 2014 ). The restoration of podocyte differentiation markers by RA has allowed this metabolite to be considered as a treatment for renal diseases ( Mallipattu and He, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

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Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes

Selma-Soriano

Llamusí

Fernández‐Costa

et al. 2020

Disease Models &Amp; Mechanisms

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Drosophila nephrocytes share functional, structural and molecular similarities with human podocytes. It is known that podocytes express the rabphilin 3A (RPH3A)-RAB3A complex, and its expression is altered in mouse and human proteinuric disease. Furthermore, we previously identified a polymorphism that suggested a role for RPH3A protein in the development of urinary albumin excretion. As endocytosis and vesicle trafficking are fundamental pathways for nephrocytes, the objective of this study was to assess the role of the RPH3A orthologue in Drosophila, Rabphilin (Rph), in the structure and function of nephrocytes. We confirmed that Rph is required for the correct function of the endocytic pathway in pericardial Drosophila nephrocytes. Knockdown of Rph reduced the expression of the cubilin and stick and stones genes, which encode proteins that are involved in protein uptake and filtration. We also found that reduced Rph expression resulted in a disappearance of the labyrinthine channel structure and a reduction in the number of endosomes, which ultimately leads to changes in the number and volume of nephrocytes. Finally, we demonstrated that the administration of retinoic acid to IR-Rph nephrocytes rescued some altered aspects, such as filtration and molecular uptake, as well as the maintenance of cell fate. According to our data, Rph is crucial for nephrocyte filtration and reabsorption, and it is required for the maintenance of the ultrastructure, integrity and differentiation of the nephrocyte.

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Section: Disease Models and Mechanismssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes

Selma-Soriano

Llamusí

Fernández‐Costa

et al. 2020

Disease Models &Amp; Mechanisms

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“…Podocyte-specific KLF15 induction in Tg26 mice attenuated podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis, and inflammation. It also improved renal function and overall survival; ADR-induced podocyte injury was also attenuated.[44]Podocyte InjuryKLF15KLF15 promotes podocyte differentiationWT and CCR5(−/−) mice were subjected to sham or 5/6 NephrectomyKLF15 expression was decreased in 5/6 nephrectomized WT animals and further decreased in CCR5(−/−) mice and this correlated with increased podocyte injury.[45]Renal Fibrosis and Interstitial InflammationKLF4KLF4 blocks epithelial to mesenchymal transition (EMT) in renal fibrosis1. Unilateral Ureteral Obstruction (UUO) model of renal fibrosisUUO treatment resulted in decreased KLF4 expression and increase in TGF-β expression in renal tissue.Over-expression of KLF4 suppressed TGF-β-induced progression of EMT in HK-2 cells.[49]2.…”

Section: Outstanding Questions and Challengesmentioning

confidence: 99%

Krϋppel-like factors (KLFs) in renal physiology and disease

2019

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Dysregulated Krϋppel-like factor (KLF) gene expression appears in many disease-associated pathologies. In this review, we discuss physiological functions of KLFs in the kidney with a focus on potential pharmacological modulation/therapeutic applications of these KLF proteins. KLF2 is critical to maintaining endothelial barrier integrity and preventing gap formations and in prevention of glomerular endothelial cell and podocyte damage in diabetic mice. KLF4 is renoprotective in the setting of AKI and is a critical regulator of proteinuria in mice and humans. KLF6 expression in podocytes preserves mitochondrial function and prevents podocyte apoptosis, while KLF5 expression prevents podocyte apoptosis by blockade of ERK/p38 MAPK pathways. KLF15 is a critical regulator of podocyte differentiation and is protective against podocyte injury. Loss of KLF4 and KLF15 promotes renal fibrosis, while fibrotic kidneys have increased KLF5 and KLF6 expression. For therapeutic modulation of KLFs, continued screening of small molecules will promote drug discoveries targeting KLF proteins.

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“…The kidney-enriched zinc finger transcription factor KLF15 belongs to a 17-member family of DNA-binding zinc finger transcription factors associated with differentiation, mitochondrial biogenesis, and cell cycle and DNA repair, a diverse set of cellular processes (54). Furthermore, previous reports have suggested that inducing podocyte-specific KLF15 attenuates kidney injury by directly and indirectly upregulating genes critical for podocyte differentiation, suggesting that KLF15 induction may be a potential strategy for treating proteinuric kidney disease (55).…”

Section: Discussionmentioning

confidence: 99%

Identification of potential therapeutic target genes in mouse mesangial cells associated with diabetic nephropathy using bioinformatics analysis

Mou¹,

Zhou²,

Liu³

et al. 2019

Exp Ther Med

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The aim of the present study was to identify genes under the effect of transforming growth factor-β (TGF-β1), high glucose (HG) and glucosamine (GlcN) in MES-13 mesangial cells and elucidate the molecular mechanisms of diabetic nephropathy (DN). The gene expression datasets GSE2557 and GSE2558 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were independently screened using the GEO2R online tool. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery. The protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape software. The hub genes were identified by the NetworkAnalyzer plugin. Overlapping genes were subjected to molecular docking analysis using SystemsDock. A total of 202 upregulated and 158 downregulated DEGs from the HG-treated groups, 138 upregulated and 103 downregulated DEGs from the GlcN-treated groups, and 81 upregulated and 44 downregulated DEGs from the TGF-β1-treated groups were identified. The majority of the DEGs were independently enriched in ‘nucleosome assembly’, ‘chromatin silencing’ and ‘xenobiotic glucuronidation’. In addition, KEGG pathways were significantly enriched in ‘systemic lupus erythematosus’, ‘protein processing in endoplasmic reticulum’ and ‘aldarate metabolism pathway’, and ‘TNF signaling pathway’ intersected in the TGF-β1-treated and HG-treated groups. In total, eight hub genes, Jun, prostaglandin-endoperoxide synthase 2 (Ptgs2), fibronectin 1 (Fn1), cyclin-dependent kinase (Cdk)2, Fos, heat shock protein family A (Hsp70) member 5 (Hspa5), Hsp90b1 and homo sapiens hypoxia upregulated 1 (Hyou1), and three overlapping genes, Ras homolog gene family, member B (RHOB), complement factor H (CFH) and Krüppel-like factor 15 (KLF15), were selected. Valsartan with RHOB, and fosinopril with CFH and KLF15 had preferential binding activity. In conclusion, Jun, Ptgs2, Fn1, Cdk2, Fos, Hspa5, Hsp90b1, Hyou1, RHOB, CFH and KLF15 may be potential therapeutic targets for mesangial cells associated with DN, which may provide insight into DN treatment strategies.

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Podocyte-Specific Induction of Krüppel-Like Factor 15 Restores Differentiation Markers and Attenuates Kidney Injury in Proteinuric Kidney Disease

Abstract: Inducing podocyte-specific attenuates kidney injury by directly and indirectly upregulating genes critical for podocyte differentiation, suggesting that induction might be a potential strategy for treating proteinuric kidney disease.

Cited by 32 publications

References 75 publications

Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes

Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes

Krϋppel-like factors (KLFs) in renal physiology and disease

Identification of potential therapeutic target genes in mouse mesangial cells associated with diabetic nephropathy using bioinformatics analysis

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