Abstract: FR-PO151

Advanced Oxidation Protein Products Aggravate Tubulointerstitial Fibrosis through PKC-Dependent Mitochondrial Injury in Early Diabetic Nephropathy

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Bai, Xiaoyan, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  • Li, Xiao, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  • Tian, Jianwei, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  • Jiao, Wan, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
Background

The accumulation of advanced oxidation protein products (AOPPs) has been regarded as an initiating factor in podocyte injuries via the protein kinase C (PKC) signaling in diabetes. Yet, mechanisms of PKC signaling activation in renal tubular cell injuries and tubulointerstitial fibrosis (TIF) remain unclear. It has been established that PKC signaling plays a critical role in triggering oxidative stress and mitochondrial injuries in multiple diseases. Herein, we hypothesized that the accumulation of AOPPs in diabetes incurs mitochondrial dysfunction and oxidative stress causing renal TIF through the PKC signaling pathway.

Methods

The functional relevance of AOPP and PKC signaling in relation to mitochondrial injury, oxidative stress and fibrosis were investigated in high glucose (HG) cultured HK-2 cells and renal tubules from diabetic rats and patients using in vitro and in vivo approaches. Biological parameters were analyzed using enzyme linked immunosorbent assay (ELISA).

Results

In vitro, HG stimulated AOPP expression and augmented PKC-mediated oxidative stress and fibrosis in proximal tubular epithelial cells (PTECs). Further, we provide mechanistic evidences that inhibition of PKCη isoform alleviated mitochondrial injuries and function, attenuated apoptosis and renal fibrosis in HG cultured AOPPs-induced PTECs. In vivo, AOPPs-induced mitochondrial injuries, apoptosis and TIF were significantly decreased by PKCη inhibition in diabetic rats. Intrarenal AOPPs accumulation correlated with oxidative stress and fibrosis in renal biopsy samples from DN patients. AOPP and PKCη expression correlate with elevated proteinuria and declined renal function in diabetic rats and DN patients.

Conclusion

We propose a novel mechanism that AOPPs trigger mitochondrial dysfunction and oxidative stress causing TIF in diabetic nephropathy through activation of the PKCη isoform of the PKC signaling.

Funding

  • Government Support - Non-U.S.