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 minute injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 minute 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 hours after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMC) 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 to transgenic and non-transgenic mice after the 10 minute 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.

Human vascular progenitor cells derived from renal arteries are endothelial-like and assist in the repair of injured renal capillary networks

“…41, 44 Imaging protocol parameters included echo time, 1085ms; repetition time 2170ms; excitation pulse angle, 60; flip angle, 30; FOV 5×4 cm; matrix size 128×96; slice thickness, 1.5mm. All images were obtained in the transverse plane.…”

Peer Review #3 of "Incidence of acute kidney disease after receiving hematopoietic stem cell transplantation: a single-center retrospective study (v0.2)"

“…CNIs could activate renin angiotensin II system (RAS), which increases phospho-c-Raf (Ser338) and Erk1/2 phosphorylation increasing extracellular matrix [15]. RAS also causes vasoconstriction of renal arterioles, inducing AKI [14,16,17]. The association between AKI and the incidence of GVHD has been reported.…”

Accessory proteins for heterotrimeric G-proteins in the kidney

“…RGS4 functions as a GAP to promote deactivation of Gα q/11 and Gα i/o subunits in a cell-type dependent manner (Bansal et al, 2007 ). In the mouse kidney, RGS4 was expressed predominantly in the renal vasculature (Siedlecki et al, 2011 ; Pang et al, 2015 ).…”

“…Smooth muscle cell (SMMC)-specific knockout of RGS4 in mice exhibited increased mortality following bilateral IRI compared to the control SMMC-Cre mice. Conversely, transgenic mice over-expressing RGS4 were protected from IRI (Pang et al, 2015 ). The loss of RGS4 following ischemia was associated with a marked reduction in total renal blood flow (Siedlecki et al, 2011 ), and reduced inflammatory cytokine production from macrophages (Pang et al, 2015 ).…”

“…Conversely, transgenic mice over-expressing RGS4 were protected from IRI (Pang et al, 2015 ). The loss of RGS4 following ischemia was associated with a marked reduction in total renal blood flow (Siedlecki et al, 2011 ), and reduced inflammatory cytokine production from macrophages (Pang et al, 2015 ). Early after reperfusion following ischemia, RGS4 competed with downstream effectors for Gα q subunits activated by ANGII to prevent the normal induction of Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) following angiotensin II-stimulated in isolated vascular smooth muscle cells (Pang et al, 2015 ).…”