Mitochondrial protease ClpP deficiency protects against tubulointerstitial damage in diabetic kidney disease

Abstract

Mitochondrial quality control (MQC) imbalance has been implicated in tubulointerstitial damage of diabetic kidney disease (DKD). The mitochondrial unfolded protein response (UPRmt) is a stress-adaptive transcriptional response required for MQC. Caseinolytic peptidase P (ClpP), the critical component of the UPRmt proteolytic system, plays an essential role in regulating mitochondrial function with both beneficial and detrimental outcomes. Still, its effects on kidney pathobiology remain unclear. Here, we observed that ClpP was distributed in renal tubules and was significantly increased in the kidneys of DKD patients and db/db mice, accompanied by increased expression of the UPRmt-related molecular chaperones heat shock protein 60 (HSP60), heat shock protein 10 (HSP10) and activating transcription factor 5 (ATF5) and positively correlated with renal oxidative stress, cell apoptosis and tubulointerstitial fibrosis. ClpP shRNA alleviated tubular cell apoptosis, oxidative damage and tubulointerstitial injury in diabetic mice. The expression of HSP60, HSP10 and ATF5 was inhibited, indicating that lowering ClpP suppressed UPRmt activation. In vitro, ClpP was localized in the mitochondria of HK-2 cells. High glucose (HG) treatment upregulated ClpP expression and UPRmt-related proteins, concurrent with enhanced mitochondrial reactive oxygen species (mtROS), fibrosis markers and apoptosis. These alterations were reduced by ClpP siRNA. Instead, ClpP overexpression further exacerbated these abnormalities in HK-2 cells, while these facilitation effects were partially reversed by UPRmt suppression. Our results indicated that ClpP deficiency ameliorated renal oxidative stress and tubulointerstitial injury in DKD by inhibiting excessive UPRmt activation. These results suggest that ClpP is a valuable therapeutic target for DKD.