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

TLDR

Renal interstitial fibrosis is a key feature of progressive chronic kidney disease, and KLF15 has been shown to suppress extracellular matrix in cardiac and mesangial cells. The study aimed to determine whether KLF15 regulates renal interstitial fibrosis. KLF15 expression was measured in 5/6 nephrectomized rats at 12 and 24 weeks, and in vitro KLF15 was over‑ or knocked‑down in NRK‑49F fibroblasts to assess effects on extracellular matrix, CTGF, and ERK/JNK signaling. KLF15 levels fell in fibrotic kidneys, its overexpression reduced basal and TGF‑β1‑induced ECM and CTGF, and TGF‑β1‑mediated ERK/JNK activation lowered KLF15 and increased ECM/CTGF, all of which were reversed by ERK1/2 and JNK inhibitors, indicating KLF15 is an antifibrotic factor acting through ERK/MAPK and JNK/MAPK pathways.

Abstract

<b><i>Background/Aims: </i></b>Renal interstitial fibrosis is a hallmark of progressive chronic kidney disease (CKD). Previous studies reported that kruppel-like factor 15 (KLF15) is an important regulator of cardiac fibrosis and could reduce the expression of extracellular matrix in mesangial cells. However, the role of this transcription factor in renal interstitial fibrosis has not been reported. <b><i>Methods: </i></b>In this study, we examined KLF15 expression in the remnant kidney of 5/6 nephrectomized rats 12 or 24 weeks after operation. In vitro we examined the effect of altered KLF15 expression on the production of extracellular matrix and the pro-fibrotic factor CTGF in rat renal fibroblasts (NRK-49F), and further explored the related mechanisms. <b><i>Results: </i></b>The level of KLF15 was drastically decreased in the renal interstitium of 5/6 nephrectomized rats with progressive interstitial fibrosis, especially at 24 weeks. Our in vitro evidence showed that overexpression of KLF15 repressed basal and transforming growth factor-β1 (TGF-β1)-induced extracellular matrix and CTGF in NRK-49F cells. In addition, TGF-β1-mediated activation of extracellular-regulated kinase (ERK) / mitogen-activated protein kinase (MAPK) and Jun N-terminal kinase (JNK) /MAPK downregulated KLF15 expression and increased the level of extracellular matrix and CTGF, and all these effects were completely abolished by ERK1/2 inhibitor and JNK inhibitor in NRK-49F cells. <b><i>Conclusions: </i></b>Our findings implicate that KLF15 plays an important role and may prove to be an antifibrotic factor in renal interstitial fibrosis through regulation of ERK/MAPK and JNK/MAPK signaling pathways.