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

Sep 8, 2020FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Reducing calcineurin 1 deficiency helps prevent kidney scarring by improving mitochondrial health

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Abstract

Conditional knockout of RCAN1 in tubular epithelial cells resulted in a marked decrease in mitochondrial fragmentation in experimental chronic kidney disease models.

Decreased tubulointerstitial fibrosis and epithelial to mesenchymal transition-like changes were observed following RCAN1 deletion after kidney injury.
RCAN1 deletion attenuated tubular apoptosis by inhibiting the cytochrome c/caspase-9 pathway.
Mitochondrial profission proteins Drp1 and Mff were downregulated in the obstructed kidneys of RCAN1-deficient mice.
RCAN1 deletion improved dysfunctional tubular autophagy by regulating the mitophagy pathway.
Knockdown and knockout of RCAN1 enhanced mitochondrial quality control in kidney cells stimulated by TGF-β1.

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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.

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

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