Renoprotective Effects of Alpha Lipoic Acid on Iron Overload-Induced Kidney Injury in Rats by Suppressing NADPH Oxidase 4 and p38 MAPK Signaling

Biol Trace Elem Res. 2020 Feb;193(2):483-493. doi: 10.1007/s12011-019-01733-3. Epub 2019 Apr 25.

Abstract

We aimed to investigate the protective effect of alpha lipoic acid (ALA), a powerful antioxidant, against oxidative kidney damage induced by iron overload in rats. Male Wistar albino rats were separated into groups: control (n = 7), ALA (100 mg/kg (n = 7), iron sucrose (IS) (40 mg/kg) (n = 7), and IS + ALA (40 mg/kg IS administration followed by 100 mg/kg ALA) (n = 7). IS and ALA were injected weekly for 4 weeks via the tail vein. Blood and kidneys were collected at sacrification on day 29. Serum creatinine and iron levels were analyzed. Tubular injury and iron deposits were evaluated histopathologically. Additionally, iron, malondialdehyde (MDA), superoxide dismutase (SOD), catalase, and glutathione (GSH) levels and mRNA expressions of the subunits of NADPH oxidase, known as NOX4 and p22phox, tumor necrosis factor (TNF)-α, kidney injury molecule-1 (KIM-1), and also p38 MAPK signaling in the kidneys, were evaluated biochemically. In the IS group, serum creatinine and iron level, tubular dilation, and loss of brush border in the kidneys were significantly higher than those of the control. Although those changes were reduced by ALA, the differences were not statistically significant. However, ALA reduced significantly MDA level and increased SOD activity in the kidney during IS administration. ALA also significantly reduced mRNA expressions of NOX4 and p22phox induced by IS, which was parallel to significant decreases of TNF-α and KIM-1 mRNA expressions. Moreover, ALA could suppress the activation of p38 MAPK during IS administration. In conclusion, ALA may be an effective strategy to attenuate in IS-induced oxidative kidney injury.

Keywords: Alpha lipoic acid; Iron; Kidney; NOX4; Oxidative stress; p38 MAPK.

MeSH terms

  • Animals
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Gene Expression / drug effects
  • Iron Overload / complications
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney Diseases / etiology
  • Kidney Diseases / metabolism
  • Kidney Diseases / prevention & control*
  • MAP Kinase Signaling System / drug effects*
  • Male
  • NADPH Oxidase 4 / antagonists & inhibitors*
  • NADPH Oxidase 4 / genetics
  • NADPH Oxidase 4 / metabolism
  • Protective Agents / pharmacology
  • Rats, Wistar
  • Thioctic Acid / pharmacology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cell Adhesion Molecules
  • Havcr1protein, rat
  • Protective Agents
  • Tumor Necrosis Factor-alpha
  • Thioctic Acid
  • NADPH Oxidase 4
  • p38 Mitogen-Activated Protein Kinases