The present application is a revision of a competing renewal. The general focus of the present application remains the same as the previous award, namely studies of the mechanisms of progressive renal injury as related to adaptive responses of the nephron. The first set of studies on the present application seeks to more completely and precisely define the mechanisms whereby alterations in glomerular hemodynamics lead to injury to residual glomeruli. Evidence has accumulated, both in the PI's investigations and those of others, that increases in transcapillary hydraulic pressure gradient are the specific injurious factor in hemodynamically mediated glomerular injury. The present proposal seeks to deepen our understanding of the effects of dietary protein on glomerular hemodynamics by studying its interaction with the renin-angiotensin system. Also, we propose to explore the effects of dietary salt on the residual nephron. This approach combines micropuncture studies of hemodynamics, macromolecular clearances, basic biochemical and morphometric analysis with dietary and pharmacologic manipulations, all aimed at elucidating the interaction of diet, renal adaptation, and glomerular injury. The present application also seeks to continue to expand the general concept that adaptive changes in residual nephron function have maladaptive consequences by investigating the role of increased renal ammoniagenesis i promoting tubulointerstitial injury. These studies focus on the relationship between elevated ammonia levels and triggering of the alternative complement pathway. Completed studies indicate that changes in ammonia production and intrarenal ammonia levels by alterations of dietary acid load can influence the degree of tubulointerstitial injury in the remnant kidney. Furthermore, these studies have indicated that this alteration may be achieved at least in part by changes in complement deposition within the tubulointerstitial compartment. Studies of the remnant model and two other models likely to be associated with tubulointerstitial injury and simultaneously high ammonia levels, namely hypokalemic nephropathy and distal renal tubular acidosis, are also proposed for investigation. Further, delineation of this reaction by in vitro studies is proposed. These studies should help to enlarge and further test the concept that adaptive changes in both glomerular and tubular function may have maladaptive consequences. These studies will lead not only to better understanding of the adaptions of the injured kidney but ultimately to the rational design of therapies to offset maladaptive consequences.
| 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 |
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