In the previous funding period, we have shown that high doses of angiotensin inhibition, linked to decreased plasminogen activator inhibitor-1 (PAI-1), could regress existing glomerulosclerosis over the short term. This regression was linked to decreased matrix and restoration of plasmin. Our new preliminary data show limited long-term efficacy over six months of this intervention, indicating limitations of blockade of only the AT1 receptor. We postulate that these limits are due to the inability of podocytes to regenerate and proliferate after injury. We therefore will now focus on the potential and mechanisms of podocyte loss and repair to allow optimal regression of existing glomerulosclerosis. Our new exciting preliminary data shows that PAI-1 deficiency protects podocytes after injury with decreased loss and preserved differentiation. Podocytes deficient in PAI-1 revealed remarkable protection with less apoptosis and preserved cytoskeleton in vitro after injury, and systemic PAI-1 knockout mice were protected from development of sclerosis. Based on these exciting new data, our new central hypothesis is that decreased PAI-1 plays a pivotal role in preventing podocyte loss. Novel exciting data implicate the parietal epithelial cell (PECs) as a niche stem cell for podocyte regeneration, and suggest that these PECS could migrate to a visceral epithelial cell location. However, it is not determined whether these migrating parietal cells contribute to repair or alternatively may promote matrix synthesis and sclerosis. We will explore the mechanisms of podocyte protection by PAI-1 deficiency, testing the hypothesis that podocyte PAI-1 deficiency maintains podocyte number and function, and that this is mediated by decrease in the urokinase type plasminogen activator receptor. We will further test the hypothesis that consequences of parietal epithelial cell transition after injury are modulated by PAI-1. We have in hand homozygous floxed mice to allow us to examine in-depth mechanisms of time-specific deletion of PAI-1 in podocytes specifically both in vivo and in vitro. We will tes these hypotheses in a primary podocyte injury model with a toxin receptor specifically expressed only on podocytes (NEP25), and in a model of secondary sclerosis induced by 5/6 nephrectomy. Together, our studies will examine the potential and mechanisms of long-term regression of glomerulosclerosis, hypothesized to be fundamentally linked to PAI-1-dependent mechanisms that decrease podocyte loss and increase podocyte regeneration.
Podocytes are key cells for glomerular function. When they are injured, they cannot easily regenerate, and glomerular scarring ensues, leading to chronic kidney disease. We find that decreasing plasminogen activator inhibitor-1 (PAI-1) can directly prevent podocyte loss and we postulate that other epithelial cells in the glomerulus can contribute to repair. We will determine the specific mechanisms and potential of podocyte replenishment and reversal of sclerosis when we specifically decrease PAI-1 in the podocytes after injury.
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