科研之友
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摘要
Aims: Diabetic nephropathy (DN) is the most common microvascular complications and the principal cause of mortality and morbidity rates in patients with diabetes. The expression of advanced oxidation protein products (AOPPs) has been found in vacuolated renal tubules in DN and correlated with patients' decreased renal function. The accumulation of AOPPs is regarded as an initiating factor in podocyte injuries via the protein kinase C (PKC) signaling, which plays a critical role in triggering oxidative stress and mitochondrial injuries in diseases including DN. Whether AOPPs could induce mitochondrial injuries and fibrosis in renal tubules remains largely unknown. Herein, we tested the hypothesis that the accumulation of AOPPs in diabetes incurs mitochondrial dysfunction and oxidative stress, causing renal tubulointerstitial fibrosis (TIF) via PKC signaling pathway. Results:In vivo, intrarenal AOPPs accumulation correlated with oxidative stress, renal fibrosis, proteinuria, and declined renal function in DN patients and diabetic rats. AOPPs-induced mitochondrial injuries, apoptosis, and TIF were significantly mitigated by PKC eta inhibition in diabetic rats. In vitro, high glucose (HG) stimulated AOPP expression and augmented PKC-mediated oxidative stress and fibrosis in HK-2 cells. Furthermore, we provide mechanistic evidence that inhibition of PKC eta isoform alleviated mitochondrial injuries and function, attenuated apoptosis, and renal fibrosis in HG-cultured AOPPs-induced HK-2 cells. Innovation and Conclusion: We propose a novel mechanism that AOPPs-induced mitochondrial dysfunction and oxidative stress cause TIF in DN via activation of the PKC eta isoform.
