Access Type

Open Access Dissertation

Date of Award

January 2011

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmacology

First Advisor

Lawrence H. Lash

Abstract

A reduction in functional renal mass occurs in humans during aging and severe kidney damage from diseases, injuries, infections and congenital conditions and after nephrectomy. Nephrectomy, or surgical removal of a kidney or a section of a kidney, is performed for treatment of unilateral secondary renal cancer, infections and for kidney transplantation. As a result, the remaining renal tissue undergoes compensatory growth due primarily to hypertrophy, in which both the size and functional capacity of the remaining kidney are increased. Renal compensatory hypertrophy is associated with a series of physiological, morphological and biochemical changes that also have toxicological implications.

Previous studies have shown that compensatory renal cellular hypertrophy after uninephrectomy resulted in a hypermetabolic state, increased glutathione (GSH) content, but higher renal oxidative stress. These changes are also associated with increased susceptibility of renal proximal tubule cells to several drugs and environmental chemicals. Furthermore, our lab also showed that overexpression of mitochondrial GSH transporters, the dicarboxylate (DIC, Slc25a10) and 2-oxoglutarate (OGC, Slc25a11) carriers, in NRK-52E cells, which are derived from normal rat kidney proximal tubules, exhibited increased mitochondrial GSH uptake, contents of GSH and protection from chemically induced apoptosis from exposure to nephrotoxicants.

Based on these previous observations, we hypothesized that compensatory renal hypertrophy after uninephrectomy alters renal function in vivo and mitochondrial status and modulation of mitochondrial redox status alters susceptibility to nephrotoxicants in the remnant kidney. In this study, we used a uninephrectomized (NPX) rat model to induce compensatory renal growth. Our results show alterations in renal physiological parameters consistent with modest renal injury, altered renal cellular energetics, upregulation of certain renal plasma membrane transporters, including some that have been observed to transport GSH, and evidence of increased oxidative stress in mitochondria from the remnant kidney of NPX rats. Our present results provide further evidence that compensatory renal hypertrophy is associated with mitochondrial hypertrophy and hyperpolarization and manipulation of mitochondrial GSH transporters in PT cells of hypertrophied kidney alters susceptibility to chemically induced injury. These studies provide additional insight into the molecular changes that occur in compensatory renal hypertrophy and should help in the development of novel therapeutic approaches for patients with reduced renal mass.

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