Abstract
Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Renal tubular epithelial cell apoptosis and tubular atrophy have been recognized as indicators of the severity and progression of DKD, while the mechanism remains elusive. Tumor necrosis factor receptor-associated protein 1 (TRAP1) plays critical roles in apoptosis. The aim of this study was to investigate the protective role TRAP1 plays in DKD and to study the potential underlying mechanisms. TRAP1 expression was decreased, and mitochondria were injured in NRK-52e cells under high-glucose (HG) conditions. The overexpression of TRAP1 ameliorated HG-induced apoptosis, increased cell viability, maintained mitochondrial morphology, adenosine triphosphate (ATP) levels, and mitochondrial membrane potential (MMP), and buffered oxidative stress, whereas TRAP1 knockdown aggravated these effects. The protective effects of TRAP1 may be exerted via the inhibition of mitochondrial permeability transition pore (mPTP) opening, and the damage caused by TRAP1 knockdown can be partially reversed by treatment with the mPTP opening inhibitor cyclosporin A (CsA). In vivo, TRAP1 expression upregulation by AAV2/9 injection prevented renal dysfunction, ameliorated histopathological changes, maintained mitochondrial morphology and function, and reduced apoptosis and reactive oxygen species (ROS) in STZ-treated DKD rats. Thus, our results suggest that TRAP1 ameliorates diabetes-induced renal injury by preventing abnormal mPTP opening and maintaining mitochondrial structure and function, which may be treated as a potential target for DKD treatment.
Highlights
Diabetic kidney disease (DKD), one of the most frequent complications of both type 1 and 2 diabetes mellitus, has become the major cause leading to chronic kidney disease and end-stage renal disease (ESRD) worldwide [1, 2]
These results show that HG, more than high osmolarity, induced mitochondrial injury in NRK-52e cells, which may be associated with the decrease in Tumor necrosis factor receptor-associated protein 1 (TRAP1) expression
CCK-8 release analysis showed that cyclosporin A (CsA) markedly reversed the TRAP1-knockdown effect on cell viability at 48 h (Figure 5(d)). These results demonstrate that TRAP1 prevents mitochondrial damage via mitochondrial permeability transition pore (mPTP) regulation and that the aggravating damage caused by TRAP1 knockdown can be partially reversed by treatment with the mPTP opening inhibitor CsA, indicating a recoverable target for DKD treatment
Summary
Diabetic kidney disease (DKD), one of the most frequent complications of both type 1 and 2 diabetes mellitus, has become the major cause leading to chronic kidney disease and end-stage renal disease (ESRD) worldwide [1, 2]. The apoptosis, rather than necrosis, of tubular epithelial cells may predominantly account for lingering tubular atrophy, which has been recognized as an indicator of renal disease severity and progression [4, 5]. Mitochondria, the “cell’s power plants,” are highly dynamic organelles that meet the metabolic demands of cells. The kidney is a mitochondrially rich and highly metabolic organ that requires a large number of mitochondria to function normally.
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