Fate of the kidney vasculature during partial neonatal ureteral obstruction

摘要

ABSTRACT Obstructive nephropathy, the leading cause of chronic kidney disease in infants and children not only impairs nephrogenesis but can also lead to progressive destruction of immature and mature nephrons via injury to the vascular, tubular, and interstitial compartments. The proposed research project is designed to identify the vascular precursors and the mechanisms whereby they repair the injured kidney, using a model of reversible partial unilateral ureteral obstruction (pUUO) in the neonatal mouse, which parallels urinary tract obstruction in the human fetus. Our preliminary data using genetic cell fate tracing techniques show that during neonatal pUUO there are severe abnormalities in the renal arterial tree followed by loss of proximal tubular and collecting duct cells. Concomitant with the nephrovascular damage, there is expansion of interstitial cells ultimately leading to fibrosis. Remarkably, upon release of obstruction, reversal of the damage occurs with regeneration of the vasculature, proximal tubules and collecting ducts. The striking recovery observed after release of ureteral obstruction requires the reenactment of developmental pathways that control cell fate, positional information and organized growth. We propose that the kidney vasculature plays a direct and central role in the ability of the kidney to regenerate and repair after injury. Therefore, in this proposal we will test the interrelated hypotheses that ureteral obstruction leads to defective vascular morphogenesis and changes in cell fate and that that RBP-J (the transcriptional effector of all the Notch receptors) not only controls the normal development of the kidney vessels, but also the fate and regeneration of the vasculature and its associated nephrons after release of obstruction. In summary, we will explore how changes in cell identity and fate create massive morphological and functional changes which in turn determine whether the tissue will be healthy or unrecoverable. Specific Aim 1 will define the vascular changes of the postnatal kidney following obstructive nephropathy and after release, Specific Aim 2 will determine the fate of vascular cells using specific Cre recombinant and fluorescent reporter mouse lines, and Specific Aim 3 will determine whether Rbp-J plays a role in the regeneration and maintenance of the renal vasculature and associated nephrons during obstruction and after its release using mice with inducible expression of Cre recombinase and concomitant fluorescent reporter expression that allows to trace the fate of the mutant cells. The proposed work will fill an important gap in our knowledge: deciphering the cellular and molecular mechanisms involved in nephrovascular repair and regeneration has potential therapeutic implications for infants and children and the growing adult population suffering from chronic kidney disease.