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 for 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 result in hypoperfusion during acute kidney injury (AKI) are unclear. 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 and organ blood flow. Whether TRP channels control neonatal renal vascular resistance and hemodynamics is unknown. The present application originates from preliminary findings suggesting that the vanilloid transient receptor potential (TRPV) subfamily, member 4 is expressed in neonatal preglomerular renal artery and arteriole myocytes and regulates myogenic vasoconstriction, regional kidney perfusion, and GFR. Data from our pilot studies also suggest that alterations in renal vascular TRPV4 channel expression are associated with kidney hypoperfusion in renal ischemia/reperfusion-induced neonatal AKI. The overarching hypothesis of this proposal is that activation of vascular myocyte TRPV4 channels contributes to neonatal renal blood flow autoregulation, and that alterations in renal vascular myocyte 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 will test the hypotheses that: 1. Intravascular pressure activates myocyte TRPV4 channels, leading to membrane depolarization and vasoconstriction in neonatal renal preglomerular arteries, 2. Myocyte TRPV4 channels regulate neonatal renal microcirculation, GFR, and electrolyte homeostasis, and 3. Renal ischemia-reperfusion in neonates upregulates arterial myocyte TRPV4 channel expression and activity, leading to hypoperfusion and a reduction in GFR. This application will identify TRPV4 channels as an important modulator of glomerular 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)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK101668-03
Application #
9084561
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Moxey-Mims, Marva M
Project Start
2014-07-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38103
Soni, Hitesh; Peixoto-Neves, Dieniffer; Buddington, Randal K et al. (2017) Adenosine A1 receptor-operated calcium entry in renal afferent arterioles is dependent on postnatal maturation of TRPC3 channels. Am J Physiol Renal Physiol 313:F1216-F1222
Soni, Hitesh; Peixoto-Neves, Dieniffer; Matthews, Anberitha T et al. (2017) TRPV4 channels contribute to renal myogenic autoregulation in neonatal pigs. Am J Physiol Renal Physiol 313:F1136-F1148
Soni, Hitesh; Adebiyi, Adebowale (2017) Early septic insult in neonatal pigs increases serum and urinary soluble Fas ligand and decreases kidney function without inducing significant renal apoptosis. Ren Fail 39:83-91
Soni, Hitesh; Adebiyi, Adebowale (2016) TRPC6 channel activation promotes neonatal glomerular mesangial cell apoptosis via calcineurin/NFAT and FasL/Fas signaling pathways. Sci Rep 6:29041