Kidney Week

Abstract: TH-PO826

Mitochondrial Quality Control Mechanisms and Fatty Acid Metabolism in Renal Cortex During the Normoalbuminuric Stage of Diabetes Mellitus

Session Information

• Health Maintenance, Nutrition, Metabolism
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Health Maintenance‚ Nutrition‚ and Metabolism

• 1400 Health Maintenance‚ Nutrition‚ and Metabolism

Authors

• Ishii, Naohito, Kitasato University, Sgamihara, Japan

Naohito Ishii,

• Carmines, Pamela K., University of Nebraska Medical Center, Omaha, Nebraska, United States

Pamela K. Carmines,

• Kurosaki, Yoshifumi, Kitasato University, Sgamihara, Japan

Yoshifumi Kurosaki,

• Imoto, Akemi, Kitasato University, Sgamihara, Japan

Akemi Imoto,

• Sugase, Taro, Seiikai Medica Clinic, Tochigi, Japan

Taro Sugase,

• Takahashi, Hiroyuki, Kitasato University, Sgamihara, Japan

Hiroyuki Takahashi,

• Yokoba, Masanori, Kitasato University, Sgamihara, Japan

Masanori Yokoba,

• Ichikawa, Takafumi, Kitasato University, Sgamihara, Japan

Takafumi Ichikawa,

• Takenaka, Tsuneo, International University of Health & Welfare, Minato-ku, Japan

Tsuneo Takenaka,

• Katagiri, Masato, Kitasato University, Sgamihara, Japan

Masato Katagiri,

Background

Oxidative stress during the normoalbuminuric stage of type 1 diabetes mellitus (DM) damages renal cortical mitochondria; hence, we aimed to determine if oxidative stress in DM triggers 1) mitochondrial fission or fusion, 2) mitophagy, and/or 3) increased fatty acid (FA) metabolism.

Methods

Rats receiving streptozotocin (STZ, 65 mg/kg i.p.) or vehicle (Sham) were left untreated or treated with telmisartan (TLM, an angiotensin receptor blocker; 10 mg/kg/d). Two weeks later, blood glucose (BG), blood pressure (BP), glomerular filtration rate (GFR), and urinary excretion of albumin (U_albV) and N-acetyl-β-D-glucosaminidase (U_NAGV) were measured, and the renal cortex was harvested for the following assays: HPLC was used to detect 3-NT (oxidative stress marker). Fission-, fusion-, and mitophagy-related proteins were quantified by Western blot. Levels of acylcarnitine (transports FA into mitochondria for β-oxidation) were calculated as total-minus-free carnitine levels measured by the enzymatic cycling method. GC was used to quantify ω3 FAs (α-linolenic acid, EPA & DHA) and ω6 FAs (linoleic acid & AA).

Results

BP, U_albV, and U_NAGV did not differ among groups. STZ rats displayed elevated BP and GFR that were unaffected by TLM. Renal cortical samples yielded the following: The ω3/ω6 FA ratio (corrected for FA intake) and 3-NT levels were increased in STZ rats (both P<0.05 vs Sham), effects that were prevented by TLM. Acylcarnitine levels in STZ rats were higher than in Sham and were further elevated in STZ+TLM (P<0.05 vs STZ alone). STZ rats displayed TLM-sensitive increases in the mitophagy-related proteins LC3-II and PINK1 (all P<0.05), but not BNIP3 dimer or p62. Drp1 (fission marker) was 3-fold higher in STZ than in Sham, with intermediate values in STZ+TLM. Mfn2 (fusion marker) did not differ among groups.

Conclusion

During the normoalbuminuric stage of DM, renal cortical mitochondria undergo enhanced fission and mitophagy, as well as increased FA metabolism with a shift toward ω3 FAs (antioxidant & vasoprotective) relative to ω6 FAs. As these effects are blunted by TLM jointly with its antioxidant effect, they are likely quality control mechanisms triggered by oxidative damage.