Details

Autor(en) / Beteiligte

• Gould, Rebecca L.
• Craig, Steven W.
• McClatchy, Susan
• Churchill, Gary A.
• Pazdro, Robert

Titel

Genetic mapping of renal glutathione suggests a novel regulatory locus on the murine X chromosome and overlap with hepatic glutathione regulation

Ist Teil von

• Free radical biology & medicine, 2021-10, Vol.174, p.28-39

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• Glutathione (GSH) is a critical cellular antioxidant that protects against byproducts of aerobic metabolism and other reactive electrophiles to prevent oxidative stress and cell death. Proper maintenance of its reduced form, GSH, in excess of its oxidized form, GSSG, prevents oxidative stress in the kidney and protects against the development of chronic kidney disease. Evidence has indicated that renal concentrations of GSH and GSSG, as well as their ratio GSH/GSSG, are moderately heritable, and past research has identified polymorphisms and candidate genes associated with these phenotypes in mice. Yet those discoveries were made with in silico mapping methods that are prone to false positives and power limitations, so the true loci and candidate genes that control renal glutathione remain unknown. The present study utilized high-resolution gene mapping with the Diversity Outbred mouse stock to identify causal loci underlying variation in renal GSH levels and redox status. Mapping output identified a suggestive locus associated with renal GSH on murine chromosome X at 51.602 Mbp, and bioinformatic analyses identified apoptosis-inducing factor mitochondria-associated 1 (Aifm1) as the most plausible candidate. Then, mapping outputs were compiled and compared against the genetic architecture of the hepatic GSH system, and we discovered a locus on murine chromosome 14 that overlaps between hepatic GSH concentrations and renal GSH redox potential. Overall, the results support our previously proposed model that the GSH redox system is regulated by both global and tissue-specific loci, vastly improving our understanding of GSH and its regulation and proposing new candidate genes for future mechanistic studies. [Display omitted] •Genetically-diverse mice exhibited considerable variation in renal GSH.•A suggestive locus on murine chromosome X was associated with renal GSH.•Bioinformatic analyses highlighted Aifm1 as best candidate gene on chromosome X.•Renal and hepatic GSH phenotypes were statistically correlated.•A locus on murine chromosome 14 is shared between renal Eh and hepatic GSH.