Pharmacological inhibition of TRPV4 channels protects against early renal hypoperfusion induced by ischemia‐reperfusion in neonatal pigs

Abstract

Renal ischemia‐reperfusion (IR) remains a significant cause of acute kidney injury (AKI) in neonates. Early renal vasoconstriction in ischemic AKI induces hypoperfusion and a rapid decline in kidney function. Mechanisms that underlie post‐ischemic renal hypoperfusion are poorly understood, but possibilities include alterations in ion channel‐mediated renal vasoregulation. Here, we show that pharmacological activation of TRPV4 channels promotes renal vasoconstriction and hypoperfusion in neonatal pigs. Bilateral renal ischemia followed by short‐term reperfusion increased TRPV4 channel protein expression and activity in preglomerular microvessels and vascular smooth muscle cells (SMCs), respectively. Renal IR caused oliguria and elevated serum or urine levels of AKI biomarkers. Renal IR also increased renal vascular resistance (RVR) and attenuated renal blood flow and glomerular filtration rate in the pigs. However, TRPV4 channel blockers HC 067047 and RN 1734 mitigated renal IR‐induced oliguria, hypoperfusion, and alterations in AKI biomarkers. Furthermore, renal IR increased serum angiotensin II (ANG II) concentration, but not renal vascular expression of type 1 ANG II receptors in the pigs. TRPV4 channel blockade reduced ANG II‐induced renal vasoconstriction, RVR increase, and renal hypoperfusion in the pigs. Together, our data suggest that increased renal vascular SMC TRPV4 channel expression, ANG II‐induced TRPV4 activation, and subsequent increase in RVR contribute to hypoperfusion and kidney insufficiency elicited by renal IR in neonatal pigs. We propose that multimodal signaling by renal vascular SMC TRPV4 channels regulates neonatal renal hemodynamics in health and disease.Support or Funding InformationR01DK101668This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.