Faculty Collaboration Database

p66Shc-mediated hydrogen peroxide production impairs nephrogenesis causing reduction of number of glomeruli. Life Sci 2021 Aug 15;279:119661

Date

06/05/2021

Pubmed ID

34087282

Pubmed Central ID

PMC8265215

DOI

10.1016/j.lfs.2021.119661

Scopus ID

2-s2.0-85107260373 (requires institutional sign-in at Scopus site)   6 Citations

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.

Author List

Miller B, Palygin O, El-Meanawy A, Mattson DL, Geurts AM, Staruschenko A, Sorokin A

Authors

Ashraf El-Meanawy MD, PhD Professor in the Medicine department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Hydrogen Peroxide
Hypertension, Renal
Kidney Glomerulus
Male
Nephritis
Nephrons
Oxidants
Rats
Src Homology 2 Domain-Containing, Transforming Protein 1