Regulation of neonatal renal hemodynamics

点击翻译按钮获取中文摘要

The differences between neonatal and adult kidneys are not limited to their sizes. At birth, the newborn kidneys are functionally immature and exhibit higher vascular resistance and lower glomerular filtration rate (GFR) compared with adults. Renal immaturity put neonates at risk of kidney injury, especially when renal hemodynamics is altered by adverse perinatal events, including hypovolemia, asphyxia, sepsis, and renal ischemia. Several areas of neonatal renal hemodynamics remain unexplored. In particular, mechanisms that control neonatal renal vascular tone and pathological alterations that underlie hypoperfusion-induced acute kidney injury (AKI) are unresolved. A growing body of evidence suggests that members of the transient receptor potential (TRP) family of ion channels contribute to the intrinsic regulation of vascular tone in adults. Whether TRP channels control neonatal renal vascular resistance and hemodynamics is unclear. The present application derives from preliminary findings suggesting that the vanilloid transient receptor potential (TRPV) subfamily, member 4 is expressed in neonatal renal preglomerular artery and arteriole myocytes and regulates renal vascular tone, kidney perfusion, and GFR. Data from our pilot studies also suggest that alterations in renal vascular TRPV4 channel expression are associated with renal ischemia/reperfusion-induced neonatal AKI. The overarching hypothesis of this proposal is that TRPV4 channels regulate neonatal renal vascular resistance and hemodynamics, and that alterations in renal vascular TRPV4 channel expression and activity amplify kidney hypoperfusion in neonatal AKI. To address this hypothesis, three Specific Aims will be studied using newborn pigs. We propose to: 1) study localization of TRPV4 channels in preglomerular vascular myocytes and test the hypothesis that these channels regulate renal vascular resistance in neonates, 2) determine the functional significance of TRPV4 channels in neonatal renal regional microcirculation, GFR, and water and electrolyte homeostasis, and 3) explore the hypothesis that renal ischemia/reperfusion in neonates alters vascular myocyte TRPV4 channel expression and activity, leading to kidney hypoperfusion and AKI. This application will identify TRPV4 as an important regulator of renal functions in neonates.