Angiotensin AT2 Receptor Stimulation is Protective in Lipopolysaccharide‐Induced Inflammation and Renal Injury

Abstract

Recently angiotensin type‐2 receptor (AT2R) activation has been shown to exert anti‐inflammatory and reno‐protective response against chronic injury. Our prior in vitro studies using the proximal tubule epithelial cells (PTECs) and macrophages revealed that prior activation of angiotensin‐II type 2 receptor (AT2R) reduces pro‐inflammatory cytokine production in response to lipopolysaccharide (LPS). However, the in vivo effects of AT2R stimulation on LPS‐mediated inflammatory renal injury are not known. The present study tests the hypothesis that AT2R activation attenuates inflammation and preserves renal structure and function in the early stages of LPS‐mediated renal injury. Mice were pretreated with vehicle or AT2R agonist C21 (300 μg/kg, i.p.) prior to LPS (5 mg/kg, i.p) challenge. Pretreatment with C21 significantly prevented the LPS‐induced increase in the levels of renal pro‐inflammatory cytokines (TNF‐α, IL‐6), TLR4 expression, and markers of renal injury (blood urea nitrogen, plasma creatinine and albuminuria). Moreover, C21 treatment also protected against LPS‐induced tubular vacuolization and tubular degeneration. Renal and circulating anti‐inflammatory IL‐10 levels were higher with C21 pretreatment at time of LPS challenge. In vitro studies in HK‐2 cells (human PTECs) demonstrate that AT2R activation directly stimulates IL‐10 production. Further, conditioned‐media derived from the C21‐treated HK‐2 cells reduced LPS‐induced TNF‐α production via IL‐10 originating from HK‐2 cells. Our findings suggest that prior activation of AT2R prevents LPS‐mediated inflammatory renal injury, possibly via an increase in renal IL‐10 production.Support or Funding InformationThis study was supported by NIH R01 grant DK61578This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.