KLF 15 Works as an Early Anti-Fibrotic Transcriptional Regulator in Ang II-Induced Renal Fibrosis via Down-Regulation of CTGF Expression

Abstract

Background/Aims: Angiotensin II (Ang II) has been regarded as an important profibrogenic cytokine in renal fibrosis. Krüppel-like factor 15 (KLF15) has been identified as an important negative transcription factor in renal fibrosis. However, little is known about the role of KLF15 in Ang II-induced renal fibrosis. Methods: In this study, we randomized mice into a control group, Ang II group or Ang II plus losartan group. KLF15 expression was examined with real-time PCR and immunofluorescence in these groups. In vitro, KLF15 expression was examined by Western blot in rat renal fibroblasts (NRK-49F) stimulated with Ang II, and the effect of altered KLF15 expression on the regulation of the profibrotic factor connective tissue growth factor (CTGF) was further explored with co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) analyses. Results: Compared with the control group, the murine model of Ang II-induced renal fibrosis demonstrated a significant decrease in renal KLF15 expression at 4 weeks and presented with progressive renal fibrosis at 6 weeks. Meanwhile, losartan, an angiotensin type 1 (AT1) receptor antagonist, effectively prevented the down-regulation of KLF15 expression induced by Ang II infusion. In vitro, NRK-49F cells stimulated with Ang II exhibited a significant decrease in KLF15 expression, accompanied by a marked increase in the expression of profibrotic factors and in the production of extracellular matrix. The up-regulation of CTGF expression induced by Ang II stimulation was inhibited by KLF15 overexpression in NRK-49F cells, and losartan treatment prevented the down-regulation of KLF15 expression and the up-regulation of CTGF expression induced by Ang II stimulation. Furthermore, CoIP and ChIP assays revealed that the transcription regulator KLF15 directly bound to the co-activator P/CAF and repressed its recruitment to the CTGF promoter. Conclusions: Ang II down-regulates KLF15 expression via the AT1 receptor, and KLF15 is likely to inhibit Ang II-induced CTGF expression by repressing the recruitment of the co-activator P/CAF to the CTGF promoter.

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

“…Ang II treatment of mice and NRK-49F cells demonstrated decreased KLF15 expression and increased CTGF expression. Over-expression of KLF15 in the NRK-49F cells prevented Ang II-induced CTGF expression by inhibiting the co-activator P/CAF recruitment to the CTGF promoter [54]. Loss of KLF15, promoted renal fibrosis in various murine models [55].…”

“…Angiotensin II (Ang II) treatment of mice resulted in renal fibrosis, with concurrent decrease in renal KLF15 expression. Lorsartan treatment reversed the effects of Ang II treatment [54]. Loss of KLF15 expression and podocyte differentiation markers during kidney disease can be restored with dexamethasone treatment.…”

“…Ang II decreased KLF15 expression in NRK-49 Cells and induced expression of pro-fibrotic proteins and extracellular matrix proteins. Over-expression of KLF16 blocked Ang II effects in NRK-49 cells.[54]2.Rat renal fibroblasts (NRK—49F) stimulated with or without Ang IIRenal Fibrosis and Interstitial InflammationKLF15KLF15 attenuates renal fibrosis by inhibiting the canonical Wnt/β-catenin pathway Foxd1-Cre Klf15 fl/fl and Foxd1-Cre Klf15 +/+ (control) mice were subjected to sham or UUO. These mice were also treated with vehicle or Ang IILoss of KLF15 in Foxd1 + stromal cells induced pro-fibrotic markers after UUO and accelerated fibrosis after Ang II treatment.Aged Foxd1-Cre Klf15 fl/fl mice demonstrated an increase in fibrotic markers with concurrent renal dysfunction.[55]Renal Fibrosis and Interstitial InflammationKLF15KLF15 regulates renal tubular interstitial injury1.…”

Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

“…Kruppel-like factor 15 (KLF15) is a transcription factor that has been shown to suppress UUO (Gu et al, 2017a) and Ang II (Gu et al, 2017b) induced renal fibrosis in mice. Of note, KLF15 expression was down-regulated in the UUO kidneys compared to the sham kidneys, which was alleviated by quisinostat administration (Figures 4A,B).…”

An Inhibition Effect on Diabetic Cardiomyopathy Fibrosis of db/db Mice through Reduction of Myocardial Protein N-glycosylation by Crude 1-DNJ Extract from Homemade <em>Bombyx Batryticatus</em> mori.L

“…In this study, we applied the hydrophilic chromatography base solid phase Lens culinaris agglutinin (LCA) lectin was with the specific recognition to fucose α 1-6 acetylglucosamine (GlcNAc) structure, especially to the core fucose α1-6 GlcNAc structure, the affinity was more than three times than the former [44].…”