Renal manifestations of hyperoxaluria include nephrolithiasis and, when extreme, interstitial scarring and loss of kidney function. Although primary hyperoxaluria is relatively rare, hyperoxaluria secondary to gastrointestinal malabsorption is not, and in both disease states oxalate-induced nephrolithiasis, nephrocalcinosis, and renal scarring can cause renal failure and death. Furthermore, calcium oxalate kidney stone formation is extremely common in the general population, and evidence suggests that minimal, perhaps transient elevations in urinary oxalate concentration may be an important risk factor in many. Since the cellular effect of oxalate appears to depend critically on the concentration, in Specific Aim #1 we propose development of a sustained and constant model of hyperoxalemia and hyperoxaluria that utilizes an osmotic microinfusion pump. The plasma oxalate will be clamped, and the resulting oxalate concentration in the cortex, medulla, and final urine will be determined. In addition, we will measure the resulting effects on renal function, urinary markers of cellular injury and oxidative stress, and histologically examine kidneys that have been exposed to these defined concentrations of oxalate, in order to correlate cellular changes with the local oxalate concentrations. Since the effect of oxalate is also critically dependent on cell type, in Specific Aim #2 a tissue culture model system will be employed to precisely define conditions under which oxalate induces oxidative stress in proximally-, distally-, and interstitially-derived cells, and determine the pathways employed.
In Specific Aim #3 we will identify cellular responses to injury, including that caused by oxalate, that might enhance crystal retention in the kidney. By integrating these 3 specific aims the most physiologically relevant cellular responses will be determined by carefully correlating the plasma and urine oxalate concentrations, the local oxalate concentrations to which renal cells are exposed in vivo, and the cellular responses to oxalate. A key feature of this grant is the inclusion of 2 investigators new to oxalosis and nephrolithiasis research. Dr. Eddie Greene will bring extensive experience from his studies of the cellular effects of oxidative stress in order to define the mechanisms whereby oxalate triggers cellular signaling pathways in renal cells. Dr. Luis Juncos has extensive experience studying the regulation of renal blood flow in vivo, and will be critical in our efforts to develop the constant infusion model of hyperoxalemia and hyperoxaluria.
| Lieske, John C; Regnier, Cynthia; Dillon, John J (2008) Use of sevelamer hydrochloride as an oxalate binder. J Urol 179:1407-10 |
| Mo, Lan; Liaw, Lucy; Evan, Andrew P et al. (2007) Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both. Am J Physiol Renal Physiol 293:F1935-43 |
| Lieske, J C; Pena de la Vega, L S; Slezak, J M et al. (2006) Renal stone epidemiology in Rochester, Minnesota: an update. Kidney Int 69:760-4 |
| Kumar, Vivek; Lieske, John C (2006) Protein regulation of intrarenal crystallization. Curr Opin Nephrol Hypertens 15:374-80 |
| Kumar, Vivek; Farell, Gerard; Yu, Shihui et al. (2006) Cell biology of pathologic renal calcification: contribution of crystal transcytosis, cell-mediated calcification, and nanoparticles. J Investig Med 54:412-24 |
| Lieske, John C; de la Vega, Lourdes S Pena; Gettman, Matthew T et al. (2006) Diabetes mellitus and the risk of urinary tract stones: a population-based case-control study. Am J Kidney Dis 48:897-904 |
| Lieske, John C; Goldfarb, David S; De Simone, Claudio et al. (2005) Use of a probiotic to decrease enteric hyperoxaluria. Kidney Int 68:1244-9 |
| Greene, Eddie L; Farell, Gerard; Yu, Shihui et al. (2005) Renal cell adaptation to oxalate. Urol Res 33:340-8 |
| Kumar, Vivek; Pena de la Vega, Lourdes; Farell, Gerard et al. (2005) Urinary macromolecular inhibition of crystal adhesion to renal epithelial cells is impaired in male stone formers. Kidney Int 68:1784-92 |
| Farell, Gerard; Huang, Erick; Kim, Soo Y et al. (2004) Modulation of proliferating renal epithelial cell affinity for calcium oxalate monohydrate crystals. J Am Soc Nephrol 15:3052-62 |
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