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.

Public Health Relevance

Alterations in renal hemodynamics are a major cause of renal failure in newborns, but inadequate knowledge of the mechanisms that control neonatal renal microcirculation limits preventive or early therapeutic strategies. In this proposal we will investigate the hypothesis that TRPV4 channels contribute to physiological maintenance of newborn renal blood flow, and that pathological changes in expression and activity of these channels amplify hypoperfusion in neonatal acute kidney injury. We anticipate that the mechanisms identified in this proposal may provide novel therapeutic targets for perinatal nephropathy.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01DK101668-01
Application #
8671975
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Moxey-Mims, Marva M
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38103