Kruppel-Like Factor 15 Modulates Renal Interstitial Fibrosis by ERK/MAPK and JNK/MAPK Pathways Regulation

Gao, Xiang; Wu, Guiqun; Gu, Xiangchen; Fu, Lili; Mei, Changlin

doi:10.1159/000355743

Cited by 760 publications

(40 citation statements)

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“…CTGF, as a promising target for the treatment of renal fibrosis, seems to be an attractive target for anti-fibrotic therapy in kidney disease [23]. KLF15, an important transcription regulator, is greatly involved in regulating fibrosis [14, 15]. Wang et al [24].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study indicated that KLF15, which is expressed in glomeruli and interstitium, is significantly down-regulated in the renal tissues of a 5/6 nephrectomised rat CKD model and that Klf15 -/- mice are more susceptible to renal fibrosis than wild-type mice [14]. Furthermore, our research group has reported the molecular mechanism of KLF15 in the regulation of TGF-β-induced renal fibrosis [15]. However, the role of KLF15 in Ang II-induced renal fibrosis is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

Kidney Blood Press Res

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

Kidney Blood Press Res

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“…A newly developed angiotensin II receptor blocker, fimasartan, has beneficial effects in reducing renal oxidative stress, inflammation, and fibrosis by inhibition of the ERK1/2 and JNK pathways and upregulation of nuclear factor erythroid 2-related factor 2 signaling in mice with unilateral ureteral obstruction (UUO) and HK-2 cells [90]. Moreover, Kruppel-like factor 15 is a major factor in renal interstitial fibrosis, and can potentially prove to be an antifibrotic factor by regulating the ERK1/2 and JNK signaling pathways [91].…”

Section: Com/cpbmentioning

confidence: 99%

Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

Luo

Shi

et al. 2016

Cell Physiol Biochem

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Tissue hypoxia/ischemia is a pathological feature of many human disorders including stroke, myocardial infarction, hypoxic/ischemic nephropathy, as well as cancer. In the kidney, the combination of limited oxygen supply to the tissues and high oxygen demand is considered the main reason for the susceptibility of the kidney to hypoxic/ischemic injury. In recent years, increasing evidence has indicated that a reduction in renal oxygen tension/blood supply plays an important role in acute kidney injury, chronic kidney disease, and renal tumorigenesis. However, the underlying signaling mechanisms, whereby hypoxia alters cellular behaviors, remain poorly understood. Mitogen-activated protein kinases (MAPKs) are key signal-transducing enzymes activated by a wide range of extracellular stimuli, including hypoxia/ischemia. There are four major family members of MAPKs: the extracellular signal-regulated kinases-1 and -2 (ERK1/2), the c-Jun N-terminal kinases (JNK), p38 MAPKs, and extracellular signal-regulated kinase-5 (ERK5/BMK1). Recent studies, including ours, suggest that these MAPKs are differentially involved in renal responses to hypoxic/ischemic stress. This review will discuss their changes in hypoxic/ischemic pathophysiology with acute kidney injury, chronic kidney diseases and renal carcinoma.

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“…KLF15 is decreased in the renal interstitium of 5/6 nephrectomized rats and has been suggested to play an antifibrotic role, as in vitro studies demonstrate that KLF15 represses TGF-β1 signaling via ERK/ MAPK and JNK/MAPK pathways (16). Two studies have addressed the role of KLF15 in glomerular cells.…”

Section: Klfs and Mitochondriamentioning

confidence: 99%