Kidney Week

Abstract: TH-OR058

Autophagy Protects Podocytes from Diabetes-Related Glomerular Endothelial Dysfunction

Session Information

• Diabetic Kidney Disease: Discovery of Molecular Mechanisms
  November 07, 2019 | Location: 207, Walter E. Washington Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Yamahara, Kosuke, Shiga University of Medical Science, Otsu, Shiga, Japan

Kosuke Yamahara, MD, PhD



2007 – 2008 Resident, Shiga University of Medical Science, Japan 2008 – 2009 Resident, Nagahama-City Hospital, 2009 – 2010 Instructor,　Shiga University of Medical Science 2010- 2014 Ph.D. -Course Student, Shiga University of Medical Science 2014- 2015 Assistant Head Physician, Otsu Municipal Hospital 2015- 2018 Visiting Research Associate, Shiga University of Medical Science 2015- 2018 Postdoctoral Fellow, University of Freiburg, Germany 2018- Clinical fellow, Shiga University of Medical Science Fellow of the Japanese Society of Internal Medicine (FJSIM) Board Certified Nephrologist Instructor of the Japanese Society of Nephrology Fellow of the Japanese Society for Dialysis Therapy

• Yoshibayashi, Mamoru, Shiga University of Medical Science, Otsu, Shiga, Japan

Mamoru Yoshibayashi,

• Kume, Shinji, Shiga University of Medical Science, Otsu, Shiga, Japan

Shinji Kume,

• Sugahara, Sho, Shiga University of Medical Science, Otsu, Shiga, Japan

Sho Sugahara,

• Yamahara, Mako, Shiga University of Medical Science, Otsu, Shiga, Japan

Mako Yamahara,

• Takeda, Naoko, Shiga University of Medical Science, Otsu, Shiga, Japan

Naoko Takeda,

• Osawa, Norihisa, Shiga University of Medical Science, Otsu, Shiga, Japan

Norihisa Osawa,

• Chin-Kanasaki, Masami, Shiga University of Medical Science, Otsu, Shiga, Japan

Masami Chin-Kanasaki,

• Yokoi, Hideki, Kyoto University Graduate School of Medicine, Kyoto City, Japan

Hideki Yokoi,

• Mukoyama, Masashi, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

Masashi Mukoyama,

• Araki, Shin-ichi, Shiga University of Medical Science, Otsu, Shiga, Japan

Shin-ichi Araki,

• Maegawa, Hiroshi, Shiga University of Medical Science, Otsu, Shiga, Japan

Hiroshi Maegawa,

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 (Atg5^f/f) mice and TM-inducible Nphs2-Cre transgenic mice. Age-matched TM-injected Atg5^f/f mice (TM-Atg5^f/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-Atg5^f/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-Atg5^f/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.