Ganesan Ramesh, Ph.D.

Research involves the role of cytokines in drug-induced acute renal failure. Plantinum-based drugs represent an important class of antitumor agents used to treat various malignancies. Despite the great efficacy, these drugs have several side effects, most notably, nephrotoxicity. Several pathways have been shown to contribute to the toxicity including formation of reactive oxygen species, direct damage to renal tubule cells and activation of systemic inflammatory cells which infiltrate and damage the kidney. Cytokines are synthezised primarily by immune cells and have plieotrophic effects on various cells. We have shown that the expression of various cytokines and chemokines including TNF-a , TGF-b , RANTES, MIP-1, MCP-1 and IL-1b are upregulated in cisplatin-induced renal failure in mice. TNF-a is known to induce apoptosis in cultured renal proximal tubule cells. Morover, TNF-a also induces expression of various downstream effector molecules like RANTES, MIP-1 and IL-1b . Using pharmacological agents, which antagonize the secretion and/or action of TNF-a , we were able to alleviate the severity of cisplatin toxicity as measured by blood urea nitrogen and changes in gene expression of cytokines suggesting the direct role of TNF-a in cisplatin induced nephrotoxicity. We are now examining the mechanism of cisplatin-induced upregulation of TNF-a expression and the role of TNF targets in producing nephrotoxicity.

W. Brian Reeves, M.D.

The laboratory research program investigates the mechanisms of epithelial cell injury in models of acute renal failure. Current interest is focused on the role of apoptotic pathways in cell death and their modulation by cellular energy stores and intracellular electrolyte homeostasis. We are also developing the ability to measure the wide-scale expression of genes within the kidney through the use of custom cDNA microarrays which are being produced in our laboratory. This technology will be used to identify genes of pathogenic or possible therapeutic and diagnostic significance in animal models of acute and chronic renal disease. Application of this information, and of this technology, to human kidney disorder is our long-term goal. We are also investigating the cellular physiology of 11b -hydroxysteroid dehydrogenase. This enzyme is a critical determinant of aldosterone actions in the kidney and may play a role in hypertension and a variety of fluid and electrolyte disorders.

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