Urinary tract obstruction causes kidney injury, which, if left uncorrected, may lead to an irreversible renal loss especially in infants. The pathophysiology of neonatal obstructive nephropathy has been a focus of considerable research interests for decades, but significant gaps in understanding include vascular mechanisms that underlie impairment of renal microcirculation. In the present application, we propose a novel concept that alterations of newborn renal vascular resistance (RVR) and perfusion by acute ureteral obstruction are mediated by reactive oxygen species-driven biosynthesis of peptidase endothelin-converting enzyme 1, which proteolytically processes multiple renal big endothelins (ET1-3) to their vasoactive isoforms. ET-derived renal diacylglycerol (DAG) activates renal vascular smooth muscle cell TRPC3 channels, leading to receptor-operated extracellular calcium entry, prolonged vasoconstriction, RVR elevation, and hypoperfusion. To investigate these concepts, we will utilize newborn pigs that are maintained under intensive care as a preclinical model for reversible urinary tract obstruction in infants. These pigs and a novel TRPC3 knockout neonatal rat strain will be used to delineate calcium-dependent signal transduction mechanisms in renal vascular smooth muscle cells that mediate 1) persistent hypoperfusion, 2) kidney injury, and 3) impaired myogenic renal autoregulation during and after acute urinary tract obstruction. The proposed studies in this application will accrue mechanistic data that will not only improve our understanding of neonatal renal vasculopathy but may lead to potential diagnostic markers or therapeutic targets for obstructive renal insufficiency in newborns.
Impaired renal microcirculation caused by urinary tract obstruction is a significant cause of childhood kidney injury. The concept that neonatal obstructive vasculopathy is associated with ET-induced activation of vascular smooth muscle TRPC3 channels is a new paradigm for understanding the pathophysiology of this important disease. The outcome of the studies proposed in this application may lead to diagnostic and therapeutic targets to prevent renal loss in newborns with urinary tract obstruction.