RCAN1.4 mediates high glucose-induced matrix production by stimulating mitochondrial fission in mesangial cells.

Hong-Min Chen,Rui Zhu,Hong Yu,Xue-Yu Sang,Jia-Jia Dai,Bai-Fang Zhang,Fang-Fang Peng

doi:10.1042/bsr20192759

Abstract

High glucose (HG)-induced mitochondrial dynamic changes and oxidative damage are closely related to the development and progression of diabetic kidney disease (DKD). Recent studies suggest that regulators of calcineurin 1 (RCAN1) is involved in the regulation of mitochondrial function in different cell types, so we investigate the role of RCAN1 in mitochondrial dynamics under HG ambience in rat glomerular mesangial cells (MCs). MCs subjected to HG exhibited an isoform-specific up-regulation of RCAN1.4 at both mRNA and protein levels. RCAN1.4 overexpression induced translocation of Dynamin related protein 1 (Drp1) to mitochondria, mitochondrial fragmentation and depolarization, accompanied by increased matrix production under normal glucose and HG ambience. In contrast, decreasing the expression of RCAN1.4 by siRNA inhibited HG-induced mitochondrial fragmentation and matrix protein up-regulation. Moreover, both mitochondrial fission inhibitor Mdivi-1 and Drp1 shRNA prevented RCAN1.4-induced fibronectin up-regulation, suggesting that RCAN1.4-induced matrix production is dependent on its modulation of mitochondrial fission. Although HG-induced RCAN1.4 up-regulation was achieved by activating calcineurin, RCAN1.4-mediated mitochondrial fragmentation and matrix production is independent of calcineurin activity. These results provide the first evidence for the HG-induced RCAN1.4 up-regulation involving increased mitochondrial fragmentation, leading to matrix protein up-regulation.

Highlights

Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus and an important cause of death in end-stage renal disease [1,2]
The expression of regulators of calcineurin 1 (RCAN1).1 can be down-regulated by high glucose (HG) in podocytes [17], while others have demonstrated that 48 h of HG treatment had no effect on mRNA levels of RCAN1.4 in mouse mesangial cell (MC) [18]
These results indicated that HG could induce rapid up-regulation of RCAN1.4 isoform at both mRNA and protein levels in MCs

Summary

Introduction

Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus and an important cause of death in end-stage renal disease [1,2]. Various clinical strategies, including glucose control, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, only delay the progress of DKD. Growing evidence suggests that high glucose (HG)-induced mitochondrial injury, especially mitochondrial dynamic changes and oxidative damage is closely related to the occurrence and development of DKD [4,5,6]. Mitochondrial dynamics is an important quality control process, regulated by a set of proteins including fusion-related protein mitofusin 1/2 (Mfn1/2) and optic atrophy 1 (Opa1), fission-related protein dynamin related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1) [9,10]. The translocation of Drp to the outer membrane receptors of mitochondria in the form of small oligomers is considered to be the necessary initial step of mitochondrial

Methods

Results

Conclusion