|The kidney and the renin-angiotensin system (RAS) are vital regulators of blood pressure and salt-water balance. In order to appropriately regulate circulatory homeostasis, the kidney must undergo normal development, in which the RAS plays a crucial role. The main effector peptide of the RAS is angiotensin II (ANG II), which governs mammalian nephrogenesis predominantly through stimulation of ANG II type 1 (AT1) receptors. Perinatal lack of AT1 receptor stimulation leads to long-term renal damage that is characterized by tubulointerstitial inflammation/fibrosis, papillary atrophy and renal vascular changes. Irreversible morphologic abnormalities are associated with a pronounced disability in urine concentration. The inadvertent use of angiotensin-converting enzyme (ACE) inhibitors or AT1 receptor blockers in pregnant women causes neonatal oliguria and renal tubular dysplasia. These findings highlight the pivotal role of the RAS in human nephrogenesis. Generally, the present study attempted to construct the sequence of early morphologic-mechanistic events in the developing kidney of the rat subjected to neonatal pharmacologic blockade of the RAS, focusing on the role of the RAS in tubulogenesis. Specifically, this study: 1) determined the time course of tubular structural and inflammatory changes in the developing renal medulla; 2) identified genes involved in the RAS-mediated developmental process of the renal medulla; 3) characterized developmental defects of the thick ascending limb of Henle (TALH); and 4) characterized developmental defects of the tubules at a subcellular level. The following methods were employed in the present study: light and electron microscopy; stereological analysis; DNA microarrays, Western blotting and immunohistochemistry; flow cytometry and spectrophotometric analysis. The present study demonstrated that pharmacologic interruption of AT1 receptor signaling in the newborn rat induces irreversible medullary tubular changes, firstly, and triggers an inflammatory response, secondly. Perturbed tubulogenesis is associated with, and may partly result from, alterations in the assembly of extracellular matrix and nephrovascular development. Neonatal lack of ANG II stimulation causes phenotypic changes in the developing TALH. Developmental defects in the TALH provide an explanatory support for the reduced sodium reabsorption and disability to concentrate urine in adult rats subjected to neonatal inhibition of the RAS. Furthermore, early structural and functional changes in the mitochondria of the developing tubular cells devoid of ANG II stimulation provide the propensity for the tubular developmental defect. Altogether, this thesis presents an advanced pathogenetic insight into the RAS-mediated renal tubulogenesis in the rat.