title: Immunosuppression preserves renal autoregulatory function and microvascular P2X(1) receptor reactivity in ANG II-hypertensive rats.
abstract: Autoregulation is critical for protecting the kidney against arterial pressure elevation and is compromised in some forms of hypertension. Evidence indicates that activated lymphocytes contribute importantly to cardiovascular injury in hypertension. We hypothesized that activated lymphocytes contribute to renal vascular dysfunction by impairing autoregulation and P2X(1) receptor signaling in ANG II-infused hypertensive rats. Male Sprague-Dawley rats receiving ANG II infusion were treated with a lymphocyte proliferation inhibitor, mycophenolate mofetil (MMF) for 2 wk. Autoregulation was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. ANG II-treated rats exhibited impaired autoregulation. At the single vessel level, pressure-mediated afferent arteriolar vasoconstriction was significantly blunted (P < 0.05 vs. control rats). At the whole kidney level, renal blood flow passively decreased as renal perfusion pressure was reduced. MMF treatment did not alter the ANG II-induced hypertensive state; however, MMF did preserve autoregulation. The autoregulatory profiles in both in vitro or in vivo settings were similar to the responses from control rats despite persistent hypertension. Autoregulatory responses are linked to P2X(1) receptor activation. Accordingly, afferent arteriolar responses to ATP and the P2X(1) receptor agonist β,γ-methylene ATP were assessed. ATP- or β,γ-methylene ATP-induced vasoconstriction was significantly attenuated in ANG II-infused hypertensive rats but was normalized by MMF treatment. Moreover, MMF prevented elevation of plasma transforming growth factor-β1 concentration and lymphocyte and macrophage infiltration in ANG II-infused kidneys. These results suggest that anti-inflammatory treatment with MMF prevents lymphocyte infiltration and preserves autoregulation in ANG II-infused hypertensive rats, likely by normalizing P2X(1) receptor activation.
authors.affiliation: Department of Physiology, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Guan
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Giddens
authors.forename: David A
authors.initials: DA
authors.lastname: Osmond
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Cook
authors.forename: Janet L
authors.initials: JL
authors.lastname: Hobbs
authors.forename: Shali
authors.initials: S
authors.lastname: Zhang
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
authors.forename: Edward W
authors.initials: EW
authors.lastname: Inscho
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000419:Albuminuria / Q000188:drug therapy; D000804:Angiotensin II; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D006706:Homeostasis; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D058474:Receptors, Purinergic P2X1 / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000097:blood
chemical_list: D007166:Immunosuppressive Agents; D058474:Receptors, Purinergic P2X1; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D000255:Adenosine Triphosphate; D009173:Mycophenolic Acid