p66Shc-mediated hydrogen peroxide production impairs nephrogenesis causing reduction of number of glomeruli

Bradley Miller, Oleg Palygin, Ashraf El-Meanawy, David L. Mattson, Aron M. Geurts, Alexander Staruschenko, Andrey Sorokin

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Adaptor protein p66Shc, encoded by Shc1 gene, contributes to the pathogenesis of oxidative stress-related diseases. p66Shc ability to promote oxidative stress-related diseases requires phosphorylation of serine 36 residue (Ser36) and depends on translocation of p66Shc to the mitochondria. We tested the hypothesis that abnormal p66Shc-mediated reactive oxygen species (ROS) production could be critically involved in nephrons development during nephrogenesis. Main methods: We have generated unique mutant rats (termed p66Shc-Del), which express endogenous p66Shc with a 9-amino acid deletion, and lack regulatory Ser36. H2O2 renal production was measured by enzymatic microelectrode biosensors. Nephron numbers in 3–5 weeks old p66Shc-Del rats were quantified using the acid maceration method. Key findings: p66Shc-Del rats, as wild type salt sensitive rats, display increased mean arterial blood pressure following chronic exposure to a high salt diet. In contrast to wild type rats, p66Shc-Del rats display increased H2O2 renal production and are characterized by a reduction in renal function. The number of glomeruli is significantly reduced in adult p66Shc-Del rats. Significance: Since low nephron number is an established risk factor for kidney disease and hypertension in humans and rodents, our data suggest that H2O2 renal production, caused by irregular signaling of p66Shc, could be critical in regulating nephrogenesis and that abnormal p66Shc signaling negatively impacts kidney development and renal function by increasing susceptibility to diabetic nephropathy and hypertension-induced nephropathy.

Original languageEnglish (US)
Article number119661
JournalLife sciences
Volume279
DOIs
StatePublished - Aug 15 2021
Externally publishedYes

Keywords

  • Cell signaling
  • Development
  • Glomeruli
  • Kidney
  • Nephrology
  • Oxidative stress
  • Shc proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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