Xiang Gao1, Guiqun Wu, Xiangchen Gu, Lili Fu, Changlin Mei. 1. Kidney Institute of PLA, Department of Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, People's Republic of China.
Abstract
BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Xiangchen Gu; Sandeep K Mallipattu; Yiqing Guo; Monica P Revelo; Jesse Pace; Timothy Miller; Xiang Gao; Mukesh K Jain; Agnieszka B Bialkowska; Vincent W Yang; John C He; Changlin Mei Journal: Kidney Int Date: 2017-06-24 Impact factor: 10.612
Authors: Sian E Piret; Ahmed A Attallah; Xiangchen Gu; Yiqing Guo; Nehaben A Gujarati; Justina Henein; Amy Zollman; Takashi Hato; Avi Ma'ayan; Monica P Revelo; Kathleen G Dickman; Chung-Hsin Chen; Chia-Tung Shun; Thomas A Rosenquist; John C He; Sandeep K Mallipattu Journal: Kidney Int Date: 2021-10-09 Impact factor: 10.612