Manipulating Podocytes to Protect Normal Glomerular Formation

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Although reduced nephron number at term birth has been linked to increased cardiovascular, renal and metabolic diseases later in life, the developmental regulation of glomeruli, the central structure of nephron, remains largely unknown. Our recent studies to assess the glomerular number in normal developing mice revealed a significant reduction in glomeruli occurring after the cessation of new glomerulogenesis, which suggests adjustment by regression of excess nephronogenesis. Podocytes have an important role in guiding glomerular formation. We hypothesize that podocytes govern glomerular growth/regression and determine the final nephron number, and increasing podocyte population or podocyte-derived VEGF promotes growth of the glomerular vasculature and lessens glomerular regression thereby increasing glomerular reserve. We will examine and quantitate the temporal, spatial and sequential changes of podocyte number and maturity, glomerular endothelial area and capillary branching pattern, glomerular number and size, as well as their relationships to angiogenic/proliferative and regression signals. Moreover, we plan to study the role of podocytes in the maturational responses to glomerular injury, and test the hypothesis that podocyte manipulation during maturational development rescues injury-induced impairment of glomerular capillary growth, lessens glomerular regression thereby preserves glomerular number and capillary network. We will further investigate the differential responses of immature superficial glomeruli vs. relatively mature deep glomeruli in response to the injuries in developing mice. For these purposes, we will use two inducible podocyte injury models, the Nphs2-hCD25 transgenic mice with LMB2 injection and puromycin aminonucleoside injury model, and two inducible podocyte-specific rescuing models with podocyte over-expression of VEGF or induction of proliferation by SV40T expression in podocytes. Each of these transgenic models has impacts preferentially on mature or immature podocytes and glomeruli. The effects of regression inhibitory agents in these injury and rescuing models will also be studied. Later consequences of changes in glomerular development will be followed. This proposal will also discuss the abnormal vs. healthy hypertrophied glomeruli due to developmental injuries and interventions to podocytes. This proposal addresses the biology and pathology of glomerular development. Study results will further our understanding of the role of podocytes in glomerular development. The work carries implication for the normal renal reserve established during development, the effective response to injurious stimuli, and the predisposition for development of cardiovascular and renal diseases in later life.