Most forms of progressive renal disease are characterized by an increase in intraglomerular capillary pressure (Pgc), also called glomerular hypertension. Regardless of the cause of renal injury, ncreased Pgc has also been shown to be a final common pathway causing progressive renal scarring. Podocytes (also called visceral glomerular epithelial cells) line the basement membrane of the glomerular capillary loops, and prevent proteinuria. However, because podocytes contain an elaborate contractile apparatus, a critical function of podocytes is to counteract and oppose intraglomerular capillary pressure. Studies have shown that podocytes are injured by increased Pgc. However, the mechanisms underlying these events are not completely defined. One mechanism is that increased Pgc causes stress-tension on podocytes, leading to injury. The overall goal of this grant is to determine how stress-tension causes podocyte injury. We have developed an in vitro model to recapitulate this, by stretching podocytes in culture. In contrast to other glomerular cells, podocytes do not proliferate. The inability to proliferate has been shown to cause glomerulosclerosis. In the first specific aim, we will test the hypothesis that stress-tension induced podocyte injury causes anti-proliferation, and induces hypertrophy. Studies have shown that inhibiting angiotensin II (ANGII) reduces glomerular pressures, and reduces glomerulosclerosis. It is not clear why ANGII is augmented by increased Pgc. In the second aim we will test the hypothesis that stress-tension increases tissue levels of ANGII and receptors in podocytes, and that excess local ANGII activity causes non-hemodynamic effects on podocytes. Studies have shown that transforming growth factor betaa (TGF-beta) causes glomerulosclerosis in states of increased Pgc. However, the mechanism underlying the increase is not known. In the third aim of this grant, we will test the hypothesis that stress-tension increases podocytes expression of TGF-beta and receptors, and if the increase is ANGII dependent or independent. Our overall goal is to delineate novel mechanisms underlying podocyte injury in renal diseases associated with increased Pgc, so that ultimately specific therapies can be designed to reduce the progression of renal disease.
| Sussman, Amy N; Sun, Tong; Krofft, Ronald M et al. (2009) SPARC accelerates disease progression in experimental crescentic glomerulonephritis. Am J Pathol 174:1827-36 |
| Durvasula, Raghu V; Shankland, Stuart J (2008) Activation of a local renin angiotensin system in podocytes by glucose. Am J Physiol Renal Physiol 294:F830-9 |
| Durvasula, Raghu V; Shankland, Stuart J (2006) Podocyte injury and targeting therapy: an update. Curr Opin Nephrol Hypertens 15:1-7 |
| Durvasula, Raghu V; Shankland, Stuart J (2006) The renin-angiotensin system in glomerular podocytes: mediator of glomerulosclerosis and link to hypertensive nephropathy. Curr Hypertens Rep 8:132-8 |
| Durvasula, Raghu V; Shankland, Stuart J (2005) Mechanical strain increases SPARC levels in podocytes: implications for glomerulosclerosis. Am J Physiol Renal Physiol 289:F577-84 |
