Loss of activator of G-protein signaling 3 impairs renal tubular regeneration following acute kidney injury in rodents. FASEB J 2011 Jun;25(6):1844-55
Date
02/24/2011Pubmed ID
21343176Pubmed Central ID
PMC3101034DOI
10.1096/fj.10-169797Scopus ID
2-s2.0-79957927714 (requires institutional sign-in at Scopus site) 37 CitationsAbstract
The intracellular mechanisms underlying renal tubular epithelial cell proliferation and tubular repair following ischemia-reperfusion injury (IRI) remain poorly understood. In this report, we demonstrate that activator of G-protein signaling 3 (AGS3), an unconventional receptor-independent regulator of heterotrimeric G-protein function, influences renal tubular regeneration following IRI. In rat kidneys exposed to IRI, there was a temporal induction in renal AGS3 protein expression that peaked 72 h after reperfusion and corresponded to the repair and recovery phase following ischemic injury. Renal AGS3 expression was localized predominantly to the recovering outer medullary proximal tubular cells and was highly coexpressed with Ki-67, a marker of cell proliferation. Kidneys from mice deficient in the expression of AGS3 exhibited impaired renal tubular recovery 7 d following IRI compared to wild-type AGS3-expressing mice. Mechanistically, genetic knockdown of endogenous AGS3 mRNA and protein in renal tubular epithelial cells reduced cell proliferation in vitro. Similar reductions in renal tubular epithelial cell proliferation were observed following incubation with gallein, a selective inhibitor of Gβγ subunit activity, and lentiviral overexpression of the carboxyl-terminus of G-protein-coupled receptor kinase 2 (GRK2ct), a scavenger of Gβγ subunits. In summary, these data suggest that AGS3 acts through a novel receptor-independent mechanism to facilitate renal tubular epithelial cell proliferation and renal tubular regeneration.
Author List
Regner KR, Nozu K, Lanier SM, Blumer JB, Avner ED, Sweeney WE Jr, Park FAuthors
Ellis D. Avner MD Professor in the Pediatrics department at Medical College of WisconsinKevin R. Regner MD Interim Chair, Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Acute Kidney InjuryAnimals
Carrier Proteins
Gene Expression Regulation
Genotype
Guanine Nucleotide Dissociation Inhibitors
Ki-67 Antigen
Kidney Tubules
Male
Mice
Mice, Inbred C57BL
Rats
Rats, Sprague-Dawley
Regeneration
Reperfusion Injury
Time Factors
