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: TH-PO958

Nrf2 Activator, RTAdh404, Attenuates Tubular Injury via Eliminating Mitochondrial ROS in Proteinuria Induced Renal Failure Mice

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Sogawa, Yuji, Kawasaki Medical School, Kurashiki, Japan
  • Nagasu, Hajime, Kawasaki Medical School, Kurashiki, Japan
  • Satoh, Minoru, Kawasaki Medical School, Kurashiki, Japan
  • Sasaki, Tamaki, Kawasaki Medical School, Kurashiki, Japan
  • Wigley, Christian, Reata Pharmaceuticals, Irving, Texas, United States
  • Meyer, Colin John, Reata Pharmaceuticals, Irving, Texas, United States
  • Kashihara, Naoki, Kawasaki Medical School, Kurashiki, Japan
Background

Severe proteinuria, including that associated with diabetic kidney diseases (DKD), leads to renal failure. Abundant proteinuria produces excessive reactive oxidative species (ROS), which trigger inflammation via mitochondrial dysfunction. Regulation of ROS is one of the potential therapeutic strategyies for DKD with proteinuria. We focused on NF-E2-related factor 2 (Nrf2), which is a master regulator for the cellular defense against oxidative stress. Nrf2 activator has a renoprotective effect by eliminating excessive ROS in ischemic-reperfusion injury. However, the mechanisms of the renoprotective effect of Nrf2 activator are not fully understood, especially in DKD. We thus investigated whether RTAdh404 attenuates proteinuria-induced renal tubular damage via mitochondrial protection.

Methods

Male ICR-derived glomerulonephritis mice (ICGN) were used. The mice were divided into three groups: ICR as a control, ICGN+Vehicle (Vehi), and ICGN+RTA dh404 (dh404). dh404 was administered orally for three weeks (dh404;10 mg/kg/day)). Serum creatinine was evaluated as a marker of a renal function. Mitochondrial function was assessed by COX staining and transmission electron microscope. Next, in vitro study, human proximal tubular epithelial cells (hPTECs) were used to determine the mechanism of renal protective effect by dh404. hPTEC were stimulated with bovine serum albumin (BSA) binding bound to free fatty acid (FFA) and treated with or without dh404 for six hours.

Results

In ICGN+Vehi groups, renal dysfunction, based on the serum creatinine was significantly exacerbated. dH404 was able to treatment attenuated renal dysfunction in ICGN mice. Then Tubulointerstitial injury and fibrotic changes were also significantly worsened in ICGN+Vehi mice. Mitochondrial respiratory enzyme and the mitochondrial formation were injured. These damages were improved in ICGN+dh404 groups. These data suggest that RTA dh404 has a renoprotective effect via mitochondrial protection. In vitro study, hPTECs stimulated with FFA+BSA increased mitochondrial ROS and decreased mitochondrial membrane potential. These changes were improved with treatment of dh404.

Conclusion

RTA dh404 attenuates proteinuria induced tubular cell injury through improvement mitochondrial function via eliminating mitochondrial ROS.

Funding

  • Commercial Support