The principal investigator's long term research objectives involve the investigation of postnatal renal development including the examination of the factors modulating newborn renal heomdynamics and function, and the processes of renal maturation to adult capability. At birth, the newborn kidney exhibits lower renal blood flow (RBF), higher renal vascular resistance (RVR), and lower glomerular filtration rate (GFR) compared to the adult. This immature functional state contributes to neonatal physiologic homeostasis, as well as pathophysiologic conditions, and impacts the clinical management of the newborn. Maturational changes of these functional elements are required for the acquisition of fully integrated, adult-capable, renal-cardiovascular function. The factors participating in renal function at birth and subsequent postnatal development, and the mechanisms mediating them, are not fully understood. Highly activated renal vasoconstrictors, such as the renin angiotensin system and renal sympathetic nerves are considered to maintain the unique conditions in the developing renal vasculature. However, counter-acting vasodilators in the developing kidney have not been found. Although the role of nitric oxide (NO) in adult renal function is well established, knowledge of its participation in developing renal function is just emerging. Preliminary studies by the principal investigator support the hypothesis that in the developing kidney, intrarenal NO has a more important functional role than the adult, counter-regulating the renal hemodynamic and GFR effects of highly activated vasoconstrictors, and that this increased activity of NO is due to distinct developmental differences in the distribution and content of the NO synthesizing enzyme, nitric oxide synthase (NOS), and its three isoforms, NOS I, II, and III, from the adult. This proposal will further examine this hypothesis by addressing the following Specific Aims: 1. Increased intrarenal NO vasoactivity counter-regulates the vasoconstriction of renal sympathetic nerves differently in the developing kidney than in the adult. The effects of in-vivo intrarenal NO synthesis inhibition will be measured following unique vasoconstrictor-specific inhibition techniques; initially with unilateral renal denervation alone, then denervation in combination with an intrarenally infused angiotensin II ATl receptor antagonist. 2. The increased NO vasoactivity in the developing kidney is due to a different localization of intrarenal nitric oxide synthase, (NOS) compared to the adult. 3. The increased NO vasoactivity in the developing kidney is due to a different quantity of intrarenal NOS compared to the adult. In these two specific aims, molecular techniques utilizing species and isoform-specific probes will characterize the intrarenal localization and quantification of the 3 NOS isoforms in the developing and adult kidney 4. The regulation of NOS by counteracting vasoconstrictors, such as the renal sympathetic nerves or renin-angiotensin system is different in the developing than the adult kidney. Combined studies will examine the regulation of intrarenal NOS by determining the effect of vasoconstrictor inhibition pretreatment, either unilateral denervation or oral administration of an ATl receptor antagonist, on NOS localization and quantity utilizing the species and isoform-specific molecular techniques.
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| Ratliff, Brian B; Sekulic, Miroslav; Rodebaugh, Justin et al. (2010) Angiotensin II regulates NOS expression in afferent arterioles of the developing porcine kidney. Pediatr Res 68:29-34 |
| Ratliff, Brian; Rodebaugh, Justin; Sekulic, Miroslav et al. (2009) Nitric oxide synthase and renin-angiotensin gene expression and NOS function in the postnatal renal resistance vasculature. Pediatr Nephrol 24:355-65 |
| Ratliff, Brian; Rodebaugh, Justin; Sekulic, Miroslav et al. (2007) Glomerular eNOS gene expression during postnatal maturation and AT1 receptor inhibition. Pediatr Nephrol 22:1135-42 |
| Khraibi, Ali A; Yu, Tianzheng; Tang, Daiyi (2003) Role of nitric oxide in the natriuretic and diuretic responses in pregnant rats. Am J Physiol Renal Physiol 285:F938-44 |
| Solhaug, M J; Kullaprawithaya, U; Dong, X Q et al. (2001) Expression of endothelial nitric oxide synthase in the postnatal developing porcine kidney. Am J Physiol Regul Integr Comp Physiol 280:R1269-75 |
| Solhaug, M J; Dong, X Q; Adelman, R D et al. (2000) Ontogeny of neuronal nitric oxide synthase, NOS I, in the developing porcine kidney. Am J Physiol Regul Integr Comp Physiol 278:R1453-9 |
