Impaired angiotensin II type 1 receptor signaling contributes to sepsis induced acute kidney injury.

Background: In sepsis-induced acute kidney injury (SIAKI), renal blood flow (RBF) may be elevated despite decreased glomerular filtration. Angiotensin-II (Ang2) reduces RBF and maintains filtration. We hypothesized sepsis reduces angiotensin type-1 receptor (AT1R) expression.Methods: We conducted a human case-control study and experimental studies in mice. Mice(n=57) underwent cecal ligation and puncture (a sepsis model) or sham operation. Another sepsis cohort(n=66) received losartan (selective AT1R antagonist), Ang2, Ang2+losartan, or vehicle. We measured cumulative urine output (UOP), RBF, blood urea nitrogen (BUN), and creatinine. We assessed AT1R expression by ELISA and immunofluorescence. A blinded pathologist evaluated tissue for ischemic injury. We also compared AT1R expression in tissue from human sepsis patients(n=7) to healthy kidneys(n=10) and non-infected critically-ill patients(n=3).Results: In septic mice, RBF doubled(p<0.001), BUN rose(p=0.004), and UOP fell(p<0.001) by 6h. Concurrently, AT1R expression fell 2-fold(p<0.001) in arterioles and macula densa. Creatinine rose by 24h(p=0.018). Sham did not alter measurements. Losartan exacerbated sepsis-induced changes in RBF, BUN, creatinine, and UOP(p≤0.001 vs. vehicle for all). We saw no histologic evidence of cortical ischemia. Ang2 prevented changes in RBF, creatinine, and urine output(p≤0.05 vs. vehicle). Co-administering losartan reversed protection. Relative to both controls, sepsis patients had low AT1R expression in arterioles and macula densa.Conclusions: Septic humans and mice decrease renal AT1R expression. In mice, Ang2 prevents functional changes while AT1R-blockade exacerbates them independent of ischemia. Reduced AT1R expression contributes to murine SIAKI and may contribute to human SIAKI.