Renal microcirculation is tightly autoregulated under physiological conditions to maintain constant renal blood flow (RBF) and hence, glomerular capillary pressure and filtration rate despite fluctuations in renal perfusion pressure. In resistance size preglomerular vessels, an increase in perfusion pressure and the accompanying vessel wall stress stimulates smooth muscle cell (SMC) membrane depolarization that activates voltage-dependent Ca2+ channels, resulting in an elevation in intracellular Ca2+ and constriction. This phenomenon, known as the myogenic response plays a significant role in renal blood flow autoregulation. A wealth of information exists on renal autoregulation in adults. However, knowledge of renal autoregulation mechanisms in neonates is very poor. Morphological and functional differences in renal system between maturational stages preclude extrapolation of the renal vascular physiology and pathology in adults to newborns. Some evidence in adult animals suggests that renal autoregulation is impaired during ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). However, the mechanism by which renal I/R impairs renal autoregulation is unclear. The present application derives from our novel preliminary findings that establish the renal autoregulation range in a translational neonatal pig model. Data from our pilot studies also suggest that an elevation in hydrogen peroxide (H2O2) production during renal I/R in neonates reduces renal autoregulation efficiency. The central hypothesis of this proposal is that renal autoregulation is ineffective following renal I/R in neonates and that I/R-induced generation of H2O2 and resulting inhibition of myogenic renal autoregulation via voltage-gated K+ (KV) channels contributes to neonatal AKI. To address this concept, two specific aims will be studied using newborn pigs. In Aim 1, we will test the hypotheses that H2O2-induced activation of KV channels and sequential renal vascular SMC hyperpolarization opposes neonatal renal myogenic autoregulation. Aim 2 will explore the hypothesis that I/R-induced generation of H2O2 and ensuing inhibition of myogenic renal autoregulation via activation of renal vascular SMC KV channels contribute to neonatal kidney injury. Understanding the pathophysiological mechanisms that underlie neonatal renal autoregulation during AKI may provide new therapeutic targets that will ameliorate the enormous burden of neonatal kidney and cardiovascular disease in the USA.
|Effective start/end date||07/01/2016 → 06/30/2018|