Loss of activator of G-protein signaling 3 impairs renal tubular regeneration following acute kidney injury in rodents

Kevin R. Regner, Kandai Nozu, Stephen M. Lanier, Joe B. Blumer, Ellis D. Avner, William E. Sweeney, Frank Park

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1844-1855
Number of pages12
JournalFASEB Journal
Volume25
Issue number6
DOIs
StatePublished - Jun 1 2011

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GTP-Binding Proteins
Acute Kidney Injury
Regeneration
Rodentia
Cell proliferation
Kidney
Reperfusion Injury
Cell Proliferation
Epithelial Cells
Repair
G-Protein-Coupled Receptor Kinase 2
Heterotrimeric GTP-Binding Proteins
Recovery
Rats
Proteins
Messenger RNA
Reperfusion
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Loss of activator of G-protein signaling 3 impairs renal tubular regeneration following acute kidney injury in rodents. / Regner, Kevin R.; Nozu, Kandai; Lanier, Stephen M.; Blumer, Joe B.; Avner, Ellis D.; Sweeney, William E.; Park, Frank.

In: FASEB Journal, Vol. 25, No. 6, 01.06.2011, p. 1844-1855.

Research output: Contribution to journalArticle

Regner, Kevin R. ; Nozu, Kandai ; Lanier, Stephen M. ; Blumer, Joe B. ; Avner, Ellis D. ; Sweeney, William E. ; Park, Frank. / Loss of activator of G-protein signaling 3 impairs renal tubular regeneration following acute kidney injury in rodents. In: FASEB Journal. 2011 ; Vol. 25, No. 6. pp. 1844-1855.
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