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Abstract: TH-OR058

Autophagy Protects Podocytes from Diabetes-Related Glomerular Endothelial Dysfunction

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Yamahara, Kosuke, Shiga University of Medical Science, Otsu, Shiga, Japan
  • Yoshibayashi, Mamoru, Shiga University of Medical Science, Otsu, Shiga, Japan
  • Kume, Shinji, Shiga University of Medical Science, Otsu, Shiga, Japan
  • Sugahara, Sho, Shiga University of Medical Science, Otsu, Shiga, Japan
  • Yamahara, Mako, Shiga University of Medical Science, Otsu, Shiga, Japan
  • Takeda, Naoko, Shiga University of Medical Science, Otsu, Shiga, Japan
  • Osawa, Norihisa, Shiga University of Medical Science, Otsu, Shiga, Japan
  • Chin-Kanasaki, Masami, Shiga University of Medical Science, Otsu, Shiga, Japan
  • Yokoi, Hideki, Kyoto University Graduate School of Medicine, Kyoto City, Japan
  • Mukoyama, Masashi, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Araki, Shin-ichi, Shiga University of Medical Science, Otsu, Shiga, Japan
  • Maegawa, Hiroshi, Shiga University of Medical Science, Otsu, Shiga, Japan
Background

In diabetic nephropathy, glomerular endothelial dysfunction is a primary event leading to albuminuria, and impaired podocyte autophagy is recently focused as a factor associated with progression to massive albuminuria. However, an interaction between these two events is still unclear. This study was designed to examine a renoprotective role of autophagy in podocyte injury during the development of diabetes-related glomerular endothelial dysfunction.

Methods

We generated tamoxifen (TM)-inducible podocyte-specific Atg5-deficient (TM-PodoAtg5KO) mice by crossbreeding Atg5-floxed (Atg5f/f) mice and TM-inducible Nphs2-Cre transgenic mice. Age-matched TM-injected Atg5f/f mice (TM-Atg5f/f) were used as the control group. Glomerular endothelial dysfunction was induced by a high-fat diet (HFD) feeding, crossbreeding with eNOS knockout mice, or an intravenous injection of neuraminidase that can remove endothelial glycocalyx.

Results

In both TM-Atg5f/f and TM-PodoAtg5KO mice, HFD-feeding induced glomerular endothelial dysfunction, which was characterized by increased urinary nitric oxide excretion, collapsed endothelial fenestrae, and decreased endothelial glycocalyx. HFD-fed TM-Atg5f/f mice showed slight albuminuria and nearly normal podocyte morphology. In contrast, HFD-fed TM-PodoAtg5KO mice developed massive albuminuria accompanied by severe podocyte injury. The severe podocyte damage in HFD-fed TM-PodoAtg5KO mice was observed in the podocytes adjacent to damaged endothelial cells. Interestingly, podocyte-specific autophagy deficiency did not exacerbated eNOS-deficiency-induced albuminuria, whereas it markedly exacerbated neuraminidase-induced albuminuria along with sever podocyte injury. Finally, we found that ER stress was accelerated in the podocytes of TM-PodoAtg5KO mice stimulated with neuraminidase, and that a treatment with molecular chaperone, TUDCA, was able to improve neuraminidase-induced severe podocyte injury in the mice.

Conclusion

Podocyte autophagy protects podocytes from diabetes-related endothelial structural dysfunction. Insufficient autophagy leads to severe podocyte injury and subsequent massive albuminuria via activation of ER stress during the development of endothelial dysfunction in diabetic nephropathy.

Funding

  • Government Support - Non-U.S.