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PPARα activation by MHY908 attenuates age-related renal inflammation through modulation of the ROS/Akt/FoxO1 pathway

Ye Ra Kim1, Eun Kyeong Lee1, Dae Hyun Kim1

  • 1Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.

Experimental Gerontology
|March 22, 2017
PubMed

Insights

MHY908 drug prevents kidney inflammation in aging rats by activating FoxO1 and inhibiting NF-κB signaling. This mechanism involves activating peroxisome proliferator-activated receptor alpha (PPARα) and reducing reactive oxygen species.

Area of Science:

  • Gerontology
  • Nephrology
  • Molecular Biology

Background:

  • Aging exacerbates insulin resistance and renal inflammation, impacting kidney function.
  • The precise mechanisms of MHY908 in mitigating age-related renal inflammation are not fully understood.
  • Insulin resistance affects signaling pathways like IRS/Akt/FoxO1 in the kidneys.

Purpose of the Study:

  • To investigate the effects of MHY908 on age-related changes in the IRS/Akt/FoxO1 signaling pathway in aged rat kidneys.
  • To elucidate the role of MHY908 in modulating renal inflammation associated with insulin resistance during aging.
  • To explore the impact of MHY908 on peroxisome proliferator-activated receptor alpha (PPARα) and reactive oxygen species (ROS) generation.

Main Methods:

  • Experiments were conducted on young rats, old rats, and old rats treated with MHY908 (1mg or 3mg/kg/day for 4 weeks).
  • HEK293T cells were used to study the effects of MHY908 on insulin-treated cells.
  • Key signaling pathways including IRS/Akt/FoxO1, NF-κB, and PPARα were analyzed.
  • Expression of MnSOD, catalase, and NADPH oxidase subunit 4 (NOX4) was measured.

Main Results:

  • MHY908 treatment in aged rats suppressed IRS/Akt phosphorylation and activated FoxO1, increasing MnSOD and catalase expression.
  • In insulin-treated cells, MHY908 prevented FoxO1 inactivation and enhanced MnSOD/catalase expression by inhibiting IRS and Akt.
  • MHY908 treatment led to decreased NF-κB signaling and activated PPARα in aged rat kidneys.
  • MHY908 attenuated NOX4-derived ROS generation and FoxO1 inactivation, suggesting PPARα activation is key.

Conclusions:

  • MHY908 ameliorates hyperinsulinemia-induced pro-inflammatory responses in aged rat kidneys.
  • The drug improves renal inflammation by inactivating NF-κB and activating FoxO1 signaling.
  • PPARα activation by MHY908 plays a critical role in reducing insulin-induced ROS generation via NOX4 inhibition.
Keywords:
AgingFoxO1InsulinMHY908PPARα

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