This application extends the PI's investigation of the factors promoting the newborn's renal condition and the regulatory mechanisms that produce postnatal renal maturation. At birth, low renal blood flow and glomerular filtration rate, promoted by high renal vascular resistance impact neonatal clinical management and predispose the newborn to develop acute renal failure, ARF, caused by adverse perinatal events. A balance between the vasoconstriction of highly activated angiotensin II, AII, and the vital counter-action of nitric oxide, NO, sustains the newborn's unique characteristics. Synchronous maturational alterations of these factors result in adult renal proficiency. NO's enhanced role in the immature kidney is due to increased expression of two isoforms of NO synthase, NOS 1 and NOS 3 compared to the adult. Both NOS isoforms undergo significant, but contrasting, postnatal expressional regulation. AII, via the AT1 receptor upregulates NOS function and expression in the postnatal developing kidney. Acute and chronic inhibition of the AII AT1 receptor produces greater attenuation of NOS functional responses in the immature kidney than the adult due to a greater downregulation of both NOS 1 and NOS 3 expression. In immature kidney slices, AII produces greater stimulation of NOS 1 and NOS3 mRNA, perhaps due to developmental differences in the influx of extracellular calcium via the L-type calcium channels, calcium influx. The hypothesis of this proposal is: The enhanced role of NO as a critical vasodilator during postnatal renal development is due to the upregulation of NOS 1 and NOS 3 expression and function by AII, via the AT1 receptor. The upregulation of NOS expression and consequent augmentation of NOS function may be due to developmentally directed mechanisms, such as extracellular calcium influx. The scientific questions and Specific Aims to be addressed by this proposal are 1. What is the pattern of the AII upregulation of NOS function during the period to postnatal maturation, and does this pattern differ between the two NOS isoforms? Specific Aim 1: To define the functional regulation of NOS 1 and NOS 3 by AII, through the AT1 receptor and determine the individual functional roles of each NOS isoform during renal development. 2. Does AII upregulate NOS 1 and NOS 3 expression coordinately during the postnatal period? Specific Aim 2: To characterize the regulation of NOS expression by AII via the AT1 receptor during the spectrum of renal maturation. 3. What are the developmentally directed mechanisms producing NOS expressional upregulation by AII? Specific Aim 3: Utilize invitro techniques to establish the mechanisms of AII upregulation of NOS 1 and NOS 3 via the AT1 receptor during postnatal maturation. Identifying the regulatory relationships between AII and NOS may lead to preventive or therapeutic measures to treat neonatal ARF.
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