Hypertension affects 25% of the world population and is a major cause of cardiac, cerebral and renal mortality, yet in 90% of cases the pathogenesis remains unknown. Recently, we proposed a pathway for the development of salt dependent hypertension in man. A major concept in the pathway is that acquired injury to the kidney results in the inability of the kidney to excrete salt, and that this is the consequence of structural (tubular, interstitial, vascular) and functional (generation of vasoactive mediators) changes. In this proposal we will specifically address aspects of this hypothesis.
In aim 1, we will determine if tubulointerstitial injury induced by phenylephrine or hypokalemia results in salt-dependent hypertension, identify the structural and functional changes in the renal tissue, and demonstrate that the hypertension can be transferred to naive animals by renal transplantation.
In aim 2 we will explore the role of osteopontin in mediating both the structural and functional changes (nitric oxide generation) in murine models of tubulointerstitial disease using knock-out and wild type mice, and will explore the regulation of nitric oxide synthesis in cultured endothelial cells by osteopontin.
In aim 3 we will address the role of various vasoactive mediators in these hypertensive models by administering agents that either stimulate or block their action. These studies should provide new insights into the pathogenesis and treatment of salt-dependent hypertension.
| Liu, Gang; Changsirikulchai, Siribha; Hudkins, Kelly L et al. (2008) Identification of platelet-derived growth factor D in human chronic allograft nephropathy. Hum Pathol 39:393-402 |
| Petermann, Arndt T; Pippin, Jeffrey; Durvasula, Raghu et al. (2005) Mechanical stretch induces podocyte hypertrophy in vitro. Kidney Int 67:157-66 |
| Vaughan, Michael R; Pippin, Jeffrey W; Griffin, Sian V et al. (2005) ATRA induces podocyte differentiation and alters nephrin and podocin expression in vitro and in vivo. Kidney Int 68:133-44 |
| Griffin, Sian V; Krofft, Ronald D; Pippin, Jeffrey W et al. (2005) Limitation of podocyte proliferation improves renal function in experimental crescentic glomerulonephritis. Kidney Int 67:977-86 |
| Griffin, Sian V; Hiromura, Keiju; Pippin, Jeffrey et al. (2004) Cyclin-dependent kinase 5 is a regulator of podocyte differentiation, proliferation, and morphology. Am J Pathol 165:1175-85 |
| Cybulsky, Andrey V; Takano, Tomoko; Papillon, Joan et al. (2004) Renal expression and activity of the germinal center kinase SK2. Am J Physiol Renal Physiol 286:F16-25 |
| Durvasula, Raghu V; Petermann, Arndt T; Hiromura, Keiju et al. (2004) Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 65:30-9 |
| Hudkins, Kelly L; Gilbertson, Debra G; Carling, Matthew et al. (2004) Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy. J Am Soc Nephrol 15:286-98 |
| Francki, Aleksandar; McClure, Timothy D; Brekken, Rolf A et al. (2004) SPARC regulates TGF-beta1-dependent signaling in primary glomerular mesangial cells. J Cell Biochem 91:915-25 |
| Petermann, Arndt; Hiromura, Keiju; Pippin, Jeffrey et al. (2004) Differential expression of d-type cyclins in podocytes in vitro and in vivo. Am J Pathol 164:1417-24 |
Showing the most recent 10 out of 150 publications
