The general goal of these studies is an understanding of the pathophysiologic mechanisms of progressive renal disease. They will concentrate on the remnant kidney model in the rat and humans with chronic renal insufficiency. We will examine the contribution of the renin- angiotensin-aldosterone system (RAAS) to progressive injury. This focus derives from our prior work and current preliminary studies examining the RAAS in this model and from a convincing body of data demonstrating a clear pathogenetic role for the RAAS in progression. In particular, our central and novel hypothesis is that aldosterone is the key element of the RAAS contributing to hypertension and glomerular injury. Our preliminary data strongly support this hypothesis. Our studies are designed to test rigorously the contribution of aldosterone to hypertension and glomerular injury in the remnant kidney model, to examine the mechanisms whereby increased aldosterone levels are generated in the model, and to assess the mechanisms whereby aldosterone provocates glomerular damage. Because of the strength of preliminary data and our view that this hypothesis holds great potential for understanding clinical progressive renal disease as well as providing therapies targeted at aldosterone, we have included a set of studies in human subjects. These studies examine with highly controlled short-term investigations in subjects with renal disease, the role of aldosterone in hypertension and glomerular barrier dysfunction. Thus, this proposal represents an integrated approach encompassing both animal and human investigations. In summary, we plan to extend our long- term investigation of basic mechanisms of progressive renal disease and concentrate on the new hypothesis that aldosterone engenders damage in the remnant kidney model and in progressive human renal disease.
| Juknevicius, Irmantas; Segal, Yoav; Kren, Stefan et al. (2004) Effect of aldosterone on renal transforming growth factor-beta. Am J Physiol Renal Physiol 286:F1059-62 |
| O'Bryan, T; Weiher, H; Rennke, H G et al. (2000) Course of renal injury in the Mpv17-deficient transgenic mouse. J Am Soc Nephrol 11:1067-74 |
| Ibrahim, H N; Hostetter, T H (2000) Role of dietary potassium in the hyperaldosteronism and hypertension of the remnant kidney model. J Am Soc Nephrol 11:625-31 |
| Kren, S; Hostetter, T H (1999) The course of the remnant kidney model in mice. Kidney Int 56:333-7 |
| Ibrahim, H N; Hostetter, T H (1998) The renin-aldosterone axis in two models of reduced renal mass in the rat. J Am Soc Nephrol 9:72-6 |
| O'Bryan, G T; Hostetter, T H (1997) The renal hemodynamic basis of diabetic nephropathy. Semin Nephrol 17:93-100 |
| Junaid, A; Rosenberg, M E; Hostetter, T H (1997) Interaction of angiotensin II and TGF-beta 1 in the rat remnant kidney. J Am Soc Nephrol 8:1732-8 |
| Greene, E L; Kren, S; Hostetter, T H (1996) Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 98:1063-8 |
| Junaid, A; Kren, S M; Rosenberg, M E et al. (1994) Physiological and structural responses to chronic experimental renal allograft injury. Am J Physiol 267:F1102-6 |
| Daniels, B S; Deen, W M; Mayer, G et al. (1993) Glomerular permeability barrier in the rat. Functional assessment by in vitro methods. J Clin Invest 92:929-36 |
Showing the most recent 10 out of 17 publications
