title: RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm.
abstract: Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 min injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 min unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury, blood flow was decreased in the inner cortex of wild-type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild-type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 h after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMCs) to secrete the macrophage chemoattractant RANTES, a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared with transgenic and non-transgenic mice after the 10 min injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation.
authors.affiliation: Renal Division, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Pang
authors.affiliation: Washington University in St Louis School of Medicine, St Louis, Missouri, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jin
authors.affiliation: Washington University in St Louis School of Medicine, St Louis, Missouri, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Proctor
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Farley
authors.affiliation: Partners Healthcare, Boston, Massachusetts, USA.
authors.forename: Nilay
authors.initials: N
authors.lastname: Roy
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Chin
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA [2] Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Vollmann
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Perro
authors.affiliation: Wesleyan University, Middletown, Connecticut, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hoffman
authors.affiliation: Renal Division, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Chung
authors.affiliation: Renal Division, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts, USA.
authors.forename: Nikita
authors.initials: N
authors.lastname: Chauhan
authors.affiliation: Renal Division, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts, USA.
authors.forename: Murti
authors.initials: M
authors.lastname: Mistri
authors.affiliation: Washington University in St Louis School of Medicine, St Louis, Missouri, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Muslin
authors.affiliation: Renal Division, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts, USA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Renal Division, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Siedlecki
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D001160:Arterioles / Q000503:physiopathology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D006801:Humans; D007672:Kidney Cortex / Q000098:blood supply* / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D014661:Vasoconstriction
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D018946:Chemokine CCL5; D020710:RGS Proteins; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; C098799:RGS4 protein