Regulators of calcineurin 1 deficiency attenuates tubulointerstitial fibrosis through improving mitochondrial fitness.

Xue-Yu Sang, Jing-Jie Xiao, Qing Liu, Rui Zhu, Jia-Jia Dai, Cheng Zhang, Hong Yu, Si-Jun Yang, Bai-Fang Zhang

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2020 Nov

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Renal fibrosis is the common pathological process of various chronic kidney diseases (CKD). Recent studies indicate that mitochondrial fragmentation is closely associated with renal fibrosis in CKD. However, the molecular mechanisms leading to mitochondrial fragmentation remain to be elucidated. The present study investigated the role of regulators of calcineurin 1 (RCAN1) in mitochondrial fission and renal interstitial fibrosis using conditional knockout mice in which RCAN1 was genetically deleted in tubular epithelial cells (TECs). TEC-specific deletion of RCAN1 attenuated tubulointerstitial fibrosis and epithelial to mesenchymal transition (EMT)-like phenotype change after unilateral ureteral obstruction (UUO) and ischemia reperfusion injury (IRI) through suppressing TGF-β1/Smad3 signaling pathway. TEC-specific deletion of RCAN1 also reduced the tubular apoptosis after UUO by inhibiting cytochrome c/caspase-9 pathway. Ultrastructure analysis revealed a marked decrease in mitochondrial fragmentation in TECs of RCAN1-deficient mice in experimental CKD models. The expression of mitochondrial profission proteins dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff) was also downregulated in obstructed kidney of TEC-specific RCAN1-deficient mice. Furthermore, TEC-specific deletion of RCAN1 attenuated the dysfunctional tubular autophagy by regulating PINK1/Parkin-induced mitophagy in CKD. RCAN1 knockdown and knockout similarly improved the mitochondrial quality control in HK-2 cells and primary cultured mouse tubular cells stimulated by TGF-β1. Put together, our data indicated that RCAN1 plays an important role in the progression of tubulointerstitial fibrosis through regulating the mitochondrial quality. Therefore, targeting RCAN1 may provide a potential therapeutic approach in CKD. © 2020 Federation of American Societies for Experimental Biology.

Citation

Xue-Yu Sang, Jing-Jie Xiao, Qing Liu, Rui Zhu, Jia-Jia Dai, Cheng Zhang, Hong Yu, Si-Jun Yang, Bai-Fang Zhang. Regulators of calcineurin 1 deficiency attenuates tubulointerstitial fibrosis through improving mitochondrial fitness. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Nov;34(11)