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Kidney Week

Abstract: PO0681

Mitophagy-Related Renal and Proximal Tubular Protection During the Normoalbuminuric Stage of Diabetes Mellitus

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ishii, Naohito, Kitasato University, Sagamihara, Japan
  • Carmines, Pamela K., University of Nebraska Medical Center, Omaha, Nebraska, United States
  • Kurosaki, Yoshifumi, Kitasato University, Sagamihara, Japan
  • Imoto, Akemi, Kitasato University, Sagamihara, Japan
  • Takahashi, Hiroyuki, Kitasato University, Sagamihara, Japan
  • Ikenaga, Hideki, Seiikai, Tochigi, Japan
  • Yokoba, Masanori, Kitasato University, Sagamihara, Japan
  • Ichikawa, Takafumi, Kitasato University, Sagamihara, Japan
  • Takenaka, Tsuneo, International University of Health & Welfare, Minato-ku, Japan
  • Katagiri, Masato, Kitasato University, Sagamihara, Japan
Background

Oxidative stress during the normoalbuminuric stage of type 1 diabetes mellitus (DM) damages renal cortical mitochondria. Because accumulation of damaged mitochondria can contribute to renal dysfunction, we aimed to determine a) if oxidative stress in DM triggers mitophagy as a mitochondrial quality control mechanism, and b) the renal cortical structures in which these events occur.

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 levels (BG), blood pressure (BP), glomerular filtration rate, and urinary excretion of albumin and N-acetyl-β-D-glucosaminidase (NAG) were measured. The oxidative stress marker, 3-nitrotyrosine (3-NT), was detected by HPLC. Mitophagy-related proteins (LC3-II, p62, PINK1, BNIP3) were quantified by Western blot and localized by immunoreactivity based on percent of cells staining with various intensities (HistoScore).

Results

STZ rats displayed hyperglycemia and hyperfiltration that were unaffected by TLM. BP, albumin excretion, and NAG excretion were similar in all groups. Renal cortical 3-NT levels were increased in STZ rats, a change that was prevented by TLM (STZ+TLM). Renal cortex from STZ rats displayed TLM-sensitive increases in LC3-II and PINK1 (all P<0.05), although BNIP3 and p62 levels did not differ among groups. HistoScore data failed to reveal mitophagy-related proteins in glomeruli. In contrast, immunoreactivity for all 4 proteins was readily evident in proximal tubules, with increased HistoScores in STZ rats; this effect was blunted in STZ+TLM rats. Mitophagy-related protein immunostaining was also apparent in distal tubules, but the Histoscores tended to be less than that of proximal tubules and were unaffected by STZ or TLM.

Conclusion

During the normoalbuminuric stage of DM, renal cortical mitophagy is most prominent in the proximal tubule. This effect is blunted by TLM in association with its antioxidant effect, suggesting a mitophagy-related proximal tubular protection mechanism triggered by oxidative damage.