title: Proximal tubule angiotensin AT2 receptors mediate an anti-inflammatory response via interleukin-10: role in renoprotection in obese rats.
abstract: The angiotensin type 2 receptor (AT2R) has been shown to lower inflammation in the kidney. However, the role of the anti-inflammatory cytokine interleukin (IL)-10 in AT2R-mediated attenuation of inflammation has not been elucidated. We hypothesized that AT2R activation is renoprotective by directly increasing the levels of anti-inflammatory cytokine IL-10 in the kidney via nitric oxide (NO) signaling. For in vitro studies, the human proximal tubule epithelial cell-line (human kidney-2 [HK-2]) was activated with lipopolysaccharide (10 μg/mL) and AT2R agonist C21 (1 μmol/L) for 24 hours, and media cytokine levels were assessed. Lipopolysaccharide modestly downregulated AT2R expression. Treatment with C21 lowered lipopolysaccharide-induced levels of both tumor necrosis factor-α and IL-6, but increased IL-10 levels. Treatment with neutralizing IL-10 antibody (1 μg/mL) or NO synthase inhibitor L-NAME (1 mmol/L) abolished this effect. For in vivo studies, prehypertensive obese Zucker rats and age-matched lean Zucker rats were treated for 2 weeks with C21 (300 μg/kg per day, IP) and AT2R antagonist (PD123319; 50 μg/kg per minute, SC infusion). Compared with lean Zucker rats, obese Zucker rats had higher levels of renal AT2R expression, tumor necrosis factor-α, and IL-6. C21 treatment decreased levels of tumor necrosis factor-α by 75% and IL-6 by 60%. Conversely, PD treatment lowered the renal IL-10 levels in obese Zucker rats by ≈60%. Renal morphometry revealed increased mesangial matrix expansion and glomerular macrophage infiltration, which was improved by C21 treatment in obese Zucker rats. Our findings suggest that proximal tubule AT2R activation is anti-inflammatory by increasing IL-10 production, which is largely NO dependent and thus offers renoprotection by preventing early inflammation-induced renal injury in obesity.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, Rm 521 Science and Research Bldg 2, University of Houston, Houston, TX 77004, USA.
authors.forename: Isha
authors.initials: I
authors.lastname: Dhande
authors.forename: Quaisar
authors.initials: Q
authors.lastname: Ali
authors.forename: Tahir
authors.initials: T
authors.lastname: Hussain
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000494:pharmacology*; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*
chemical_list: D044139:Receptor, Angiotensin, Type 2; D016753:Interleukin-10
keywords: AT2 Receptor; C21; anti-inflammatory; interleukin-10; nitric oxide; renoprotection
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