Despite relief, urinary tract obstruction in newborns may result in a prolonged increase in renal vascular resistance (RVR) and impaired microcirculation. The pathophysiology of renal hypoperfusion in urinary obstruction has been of significant basic and clinical research interests for decades, but major gaps in understanding include mechanisms that underlie RVR alterations in newborns, the group most adversely affected by congenital or acquired blockage of urine flow. In the present application, we propose a novel concept that an impairment of newborn renal microcirculation during, and post-acute ureteral obstruction is mediated by reactive oxygen species-driven peptidase endothelin-converting enzyme (ECE 1) biosynthesis, which converts multiple big endothelins (ET1-3) to vasoactive isoforms. ET-derived diacylglycerol (DAG) then activates the transient receptor potential cation channel subfamily C member 3 (TRPC3) in vascular smooth muscle cells, leading to renal vasoconstriction, RVR increase, and hypoperfusion. To investigate these concepts, we will utilize newborn pigs that are maintained under intensive care as a translational model of urinary obstruction. 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) prolonged hypoperfusion, 2) organ injury, and 3) impaired myogenic autoregulation during and after urinary tract obstruction. The proposed studies will accrue mechanistic data that will not only improve our understanding of neonatal renal microcirculation 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.
