title: RGS4, a GTPase activator, improves renal function in ischemia-reperfusion injury.
abstract: Acute kidney dysfunction after ischemia-reperfusion injury (IRI) may be a consequence of persistent intrarenal vasoconstriction. Regulators of G-protein signaling (RGSs) are GTPase activators of heterotrimeric G proteins that can regulate vascular tone. RGS4 is expressed in vascular smooth muscle cells in the kidney; however, its protein levels are low in many tissues due to N-end rule-mediated polyubiquitination and proteasomal degradation. Here, we define the role of RGS4 using a mouse model of IRI comparing wild-type (WT) with RGS4-knockout mice. These knockout mice were highly sensitized to the development of renal dysfunction following injury exhibiting reduced renal blood flow as measured by laser-Doppler flowmetry. The kidneys from knockout mice had increased renal vasoconstriction in response to endothelin-1 infusion ex vivo. The intrinsic renal activity of RGS4 was measured following syngeneic kidney transplantation, a model of cold renal IRI. The kidneys transplanted between knockout and WT mice had significantly reduced reperfusion blood flow and increased renal cell death. WT mice administered MG-132 (a proteasomal inhibitor of the N-end rule pathway) resulted in increased renal RGS4 protein and in an inhibition of renal dysfunction after IRI in WT but not in knockout mice. Thus, RGS4 antagonizes the development of renal dysfunction in response to IRI.
authors.affiliation: Nephrology Division, John Milliken Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA. asiedlec@dom.wustl.edu
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Siedlecki
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jin
authors.forename: Winston
authors.initials: W
authors.lastname: Thomas
authors.forename: Keith A
authors.initials: KA
authors.lastname: Hruska
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Muslin
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology / Q000601:surgery; D016030:Kidney Transplantation; D017078:Laser-Doppler Flowmetry; D007976:Leupeptins / Q000494:pharmacology; D008026:Ligation; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D020710:RGS Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D019332:Endothelin-1; D007976:Leupeptins; D061988:Proteasome Inhibitors; D020710:RGS Proteins; D014662:Vasoconstrictor Agents; C098799:RGS4 protein; D046988:Proteasome Endopeptidase Complex; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde