Profibrotic IHG-1 complexes with renal disease associated HSPA5 and TRAP1 in mitochondria

Abstract

The highly conserved mitochondrial protein induced in high glucose-1 (IHG-1) functions to maintain mitochondrial quality and is associated with the development of fibrosis in diabetic nephropathy. Towards identifying novel approaches to treating diabetic kidney disease, IHG-1-protein-protein interactions were investigated using epitope-tagged immunoprecipitation analyses followed by mass spectrometry. Here we show that IHG-1 is solely expressed in mitochondria and localised to the inner mitochondrial membrane, the region where mitochondrial reactive oxygen species are generated. Chaperones HSPA5 and TRAP1 and cold shock protein YBX1 were identified as IHG-1 binding partners. All three proteins are important in the cellular response to oxidative stress and play important roles in mitochondrial transcription and DNA repair. Both redox imbalance and IHG-1 stimulate TGF-β signalling. IHG-1, HSPA5 and YBX1 all show increased expression in diabetic nephropathy, chronic kidney disease and in the Unilateral Ureteral Obstruction model of kidney fibrosis. Increased IHG-1 expression in UUO correlated with loss of TRAP1 expression. IHG-1 may target TRAP1 for degradation. When IHG-1 is no longer localised to mitochondria, it retains the ability to interact with the cold shock protein YBX1, facilitating anti-fibrotic actions in the nucleus. Targeting these proteins may offer alternative treatments for fibrotic kidney disease.

TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria

“…Targeted regulation of TRAP1 is currently of great interest in tumor therapy (14,15). Although studies of this protein in fibrosis diseases are few, it may play important roles (16). In the present study, UUOtreated kidneys did not result in changes in TRAP1 expression in renal tubular cells, which suggests that the maintenance of TRAP1 in UUO mice is involved in the defense against renal injury.…”

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

“…Whole mitochondrial genome sequencing data from patients with IgAN who were renal transplant recipients revealed an association between five common single-nucleotide polymorphisms and ESRD, suggesting that mitochondrial defects play a potential role in the progression of CKD [73]. Interestingly, higher expression and interaction between the mitochondrial protein induced in high glucose-1 (IHG-1) and cold shock protein Y-box binding protein 1 are associated with renal inflammation, TIF, and glomerulosclerosis in IgAN [74]. These findings suggest that defects in the mitochondrial genome and functions play a critical role in worsening glomerular inflammation and disease progression.…”

Glucose-regulated protein 78 modulates cell growth, epithelial–mesenchymal transition, and oxidative stress in the hyperplastic prostate

“…Also, GRP78 has been correlated with OS. In chronic kidney disease, GRP78 was overexpressed to counteract OS damage and produce an important protective effect [ 25 ]. In vascular endothelial cells, copper oxide nanoparticles (CuONPs)-induced OS leads to upregulation of GRP78 [ 26 ].…”