ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO2012

Mitochondrial Quality Control Mechanisms in Renal Cortex During the Normoalbuminuric Stage of Diabetes Mellitus

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1300 Health Maintenance, Nutrition, and Metabolism

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
  • Ikenaga, Hideki, Seiikai, Tochigi, Japan
  • Yokoba, Masanori, Kitasato University, Sagamihara, Japan
  • Ichikawa, Takafumi, Kitasato University, Sagamihara, Japan
  • Takenaka, Tsuneo, International University of Health & Welfare, Minatoku, 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 if oxidative stress in DM triggers 1) mitochondrial fission or fusion, 2) increased fatty acid metabolism, and/or 3) mitophagy as quality control mechanisms.

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. Fission-, fusion-, and mitophagy-related proteins were quantified by Western blot. Levels of acylcarnitine, which transports fatty acids into mitochondria for β-oxidation, were calculated as the difference between total and free carnitine levels measured by the enzymatic cycling method using commercial kits.

Results

TZ 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 cortical acylcarnitine levels in STZ rats were more than double those of Sham rats (P<0.05) and were further elevated in STZ+TLM rats (P<0.05 vs STZ alone). 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, with STZ+TLM rats exhibiting intermediate levels of this fission marker. Levels of the fusion marker Mfn2, and mitophagy-related proteins BNIP3 (dimer) and p62 did not differ among groups.

Conclusion

During the normoalbuminuric stage of DM, renal cortical mitochondria undergo increased fatty metabolism, as well as enhanced fission and mitophagy that are blunted by TLM in association with its antioxidant effect and, thus, are likely quality control mechanisms triggered by oxidative damage.