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Kidney Week

Abstract: SA-PO091

PPARα in Proximal Tubules Attenuates Ischemic AKI

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Nimura, Takayuki, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Aomura, Daiki, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Yamada, Yosuke, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Harada, Makoto, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Hashimoto, Koji, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Yanagita, Motoko, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto, Japan
  • Kamijo, Yuji, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
Background

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor. The renal expression of PPARα is mainly localized in the proximal tubules (PTs). PPARα maintains tissue energy metabolism by regulating fatty acid oxidation (FAO), with several studies reporting a possible renoprotective effect of systemic PPARα against ischemic kidney injury. Since the contribution of renal PPARα to this function is unknown, we addressed the above notion using PT-specific PPARα knock-out mice.

Methods

Mice harboring Ndrg1-CreERT2 transgenes were crossed with Ppara flox/flox mice to generate Ndrg1-CreERT2-Ppara flox/flox (PTs-PPARα-CKO) mice, which were intraperitoneally injected with tamoxifen for 3 days to knock out PT PPARα. Then, bilateral 40-minute ischemia-reperfusion (I/R) was conducted on tamoxifen-treated 13-week-old Ppara flox/flox mice (controls) and PTs-PPARα-CKO mice to produce an ischemic acute kidney injury model (n=9 in both groups). A sham operation was also performed (n=3 in each group). All mice were sacrificed 24 hours after I/R or the sham operation.

Results

A deficiency in renal PPARα expression was confirmed in the PTs-PPARα-CKO mice for both I/R and sham procedures. PTs-PPARα-CKO animals subjected to I/R showed significantly higher serum creatinine levels, with pathological findings of more severe renal tubular injury than in controls. Renal cytokine expressions were also significantly higher for PTs-PPARα-CKO with I/R. Although the renal expressions of FAO-related genes were decreased by I/R in both mice groups, those depletions were significantly more severe in the PTs-PPARα-CKO mice. The renal expressions of anti-oxidative stress enzymes were also significantly lower in the PTs-PPARα-CKO mice with I/R versus controls.

Conclusion

PPARα in PTs attenuates ischemic acute kidney injury, presumably through the maintenance of renal FAO and anti-oxidative enzyme expression.