Date of Award

Spring 2006

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program/Concentration

Biomedical Sciences

Committee Director

Michael Solhaug

Committee Member

Patricia Pleban

Committee Member

Ali Khraibi

Committee Member

Russell Prewitt

Abstract

The newborn kidney is vulnerable to vasomotor acute renal failure (ARF) from adverse perinatal events or complications of prematurity. Nitric oxide (NO) vasodilation is vitally protective in this type of ARF, but its relationship with other vasoactive factors, such as angiotensin II (AII) has not been examined. In the immature kidney, nitric oxide synthase (NOS) isoforms, specifically eNOS and nNOS, are developmentally regulated, but their specific role and regulation are unknown.

The enhanced vasodilatory role of NO in the immature kidney was hypothesized to be attributed to regulatory, expressional, and functional differences in eNOS and nNOS isoforms from the adult. The objective of the dissertation was to: (1) determine which NOS isoform regulates immature renal hemodynamics by using functional whole animal studies utilizing intrarenal infusion of NOS inhibitors; (2) continue characterization of NOS expression in immature renal microstructures utilizing LCM (glomerular eNOS expression); (3) characterize expression and functional patterns of NOS isoforms, renin, and AT1 and AT2 receptors in immature preglomerular resistance microvessels utilizing novel microdissection techniques; and (4) determine AII regulation of NOS expression and function in the immature renal vasculature using AT1 and AT2 receptor inhibitors.

Isoform specific inhibition demonstrated nNOS is the major NOS isoform regulating neonatal, but not adult, renal hemodynamics. nNOS expression, greatest in the newborn's preglomerular resistance microvessels, decreased, while eNOS expression increased, with maturation. NOS enzymatic activity was greater in the neonate's preglomerular resistance microvessels, than in the adult's. AT1 and AT2 receptor inhibition demonstrated AII regulation of neonatal NOS expression and function via both receptors. Newborn nNOS expression demonstrated enhanced sensitivity to AII receptor inhibition.

Dissertation conclusions include: nNOS is the major isoform regulating renal hemodynamics in the immature, but not the mature, kidney. Glomerular eNOS expression is developmentally regulated with differences between intracortical location of glomeruli. NOS enzymatic activity in preglomerular resistance microvessels is greater in the newborn, than in the adult, and may be due to upregulated nNOS expression. While AII regulates eNOS expression and NOS enzymatic activity, via AT1 and AT2 receptors, in newborn and adult preglomerular resistance microvessels, nNOS expression is regulated by AII only in the newborn.

Comments

A Dissertation Submitted to the Faculty of Old Dominion University and Eastern Virginia Medical School in partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy in Biomedical Sciences.

DOI

10.25777/2exm-8s57

ISBN

9780542580093

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