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Abstract: TH-PO618

Renal Cortical Mitochondrial Dynamics and Elimination During the Normoalbuminuric Stage of Diabetes Mellitus

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1301 Health Maintenance, Nutrition, and Metabolism: Basic

Authors

  • Ishii, Naohito, Kitasato University, Sagamihara, KANAGAWA, Japan
  • Carmines, Pamela K., University of Nebraska College of Medicine, Omaha, Nebraska, United States
  • Imoto, Akemi, Kitasato University, Sagamihara, KANAGAWA, Japan
  • Kurosaki, Yoshifumi, Kitasato University, Sagamihara, KANAGAWA, Japan
  • Ikenaga, Hideki, Seiikai, Otawara, TOCHIGI, Japan
  • Ojima, Hajime, Kitasato University, Sagamihara, KANAGAWA, Japan
  • Yokoba, Masanori, Kitasato University, Sagamihara, KANAGAWA, Japan
  • Takenaka, Tsuneo, International University of Health and Welfare, Sanno Hospital, Tokyo, Japan
  • Katagiri, Masato, Kitasato University, Sagamihara, KANAGAWA, Japan
Background

Oxidative stress during the normoalbuminuric stage of type 1 diabetes mellitus (DM) damages renal cortical mitochondria (Clin Sci 124:543-52, 2013). Because accumulation of damaged mitochondria can contribute to renal dysfunction, we aimed to determine if oxidative stress in DM triggers renal cortical mitochondrial fission, fusion and elimination through mitochondria-selective autophagy (mitophagy).

Methods

Rats receiving i.p. injection of streptozotocin (STZ, 65 mg/kg) or vehicle (Sham) were either left untreated or treated with telmisartan (TLM, an angiotensin receptor blocker; 10 mg/kg/d). Two weeks later, blood glucose concentration (BG), blood pressure (BP), glomerular filtration rate (GFR), and urinary excretion of albumin and N-acetyl-β-D-glucosaminidase (NAG) were measured. Renal cortical 3-nitrotyrosine (3-NT; an oxidative stress marker) was detected by HPLC. Fission-, fusion-, and mitophagy-related proteins were quantified in renal cortical homogenates by Western blot and localized by immunohistochemistry.

Results

STZ rats displayed hyperglycemia that was unaffected by TLM. BP, albumin excretion, and NAG excretion were similar in all groups. Compared with Sham rats, GFR and renal cortical 3-NT levels were increased in STZ rats, and both changes were prevented by TLM. Renal cortex from STZ rats displayed TLM-sensitive increases in the mitophagy-related proteins LC3-II and PINK1 (all P<0.05). Renal cortical Drp1 levels were 3-fold higher in STZ than in Sham rats, with STZ+TLM rats exhibiting intermediate levels of this fission marker. In contrast, levels of the fusion marker Mfn2, and mitophagy-related proteins BNIP3 (dimer) and p62 levels did not differ among groups. Immunohistochemical staining confirmed that the mitophagy-related proteins in STZ were located at renal tubular sites.

Conclusion

These data suggest that fission, but not fusion, of renal cortical damaged mitochondria is enhanced by in DM. TLM-sensitive accumulation of PINK 1 and LC3-II the tubular epithelium during DM suggests that oxidative stress activates the PINK1-parkin pathway, in which PINK1 binding to LC3-II (an established marker for autophagosome formation) results in mitochondrial elimination via autophagy.

Funding

  • Government Support - Non-U.S.