Endothelins contribute to early renal insufficiency engendered by acute urinary tract obstruction in neonatal pigs

Abstract

Urinary tract obstruction reduces kidney functions, which, if left uncorrected, may lead to irreversible renal loss, especially in infants. Despite the removal of obstruction, a decline in steady‐state renal blood flow (RBF) persists, vascular mechanisms of which are poorly understood. Urinary tract obstruction‐induced increase in the levels of vasoactive endothelin (ET)‐1 has been reported in humans and rodents. However, whether obstructive renal vasculopathy is associated with increased renal production of all ET isoforms (ET1‐3) remains unresolved. Also, the mechanisms that underlie ET‐induced renal vasoregulation in neonates are unclear. Here, we show that ET receptor (ETR)‐operated calcium entry via TRPC3 channels increases renal vascular resistance and reduces RBF in neonatal pigs. Acute unilateral urinary tract obstruction (UUO) in neonatal pigs increased peptidase endothelin converting enzyme 1 (ECE1)‐dependent renal production of ET1‐3 and diacylglycerol (DAG). Despite the removal of obstruction, acute UUO reduced kidney perfusion and caused an increase in renal vascular resistance (RVR) and the urinary levels of NGAL, the early predictive biomarker of acute kidney injury. The protein expression levels of ETRs (ETA and ETB) and TRPC3 channels in renal microvessels were unaltered in neonatal pigs subjected to acute UUO. However, pharmacological inhibition of ECE1, ETR, and TRPC3 mitigated acute UUO‐induced increase in RVR and urine NGAL in the pigs. These data suggest that increased ECE1 production and proteolytic processing of all big ETs to their vasoactive isoforms contribute to early neonatal renal insufficiency engendered by UUO. ET‐derived DAG activates renal vascular smooth muscle cell TRPC3 channels, leading to extracellular calcium entry, vasoconstriction, increased RVR and sustained hypoperfusionSupport or Funding InformationNIH/NIDDK: R01DK101668 and R56DK120595