Michael Goligorsky, M.D., Ph.D.
Renal Research Institute
The major direction of the Renal Research Institute is to characterize the mechanisms of endothelial dysfunction as a harbinger of atherosclerotic, diabetic, and hypertensive vascular damage. Of note, patients with chronic kidney disease are characterized by a 20-30-fold higher risk of cardiovascular mortality than age-matched general population. Endothelial nitric oxide synthase, its expression and activity, represents the main parameter affected early during development of endothelial dysfunction, and therefore offers an opportunity to diagnose these conditions at a stage, when clinical manifestations are still absent. These studies are conducted along the following main topics:
- Homocysteine and asymmetric dimethylarginine, both metabolites accumulating in patients with end-stage renal disease and felt to be responsible for the increased frequency of atherosclerotic coronary artery disease, interfere with the activity of endothelial nitric oxide synthase. DNA microarray analysis revealed a panoply of genes turned on or off by these metabolites. Studies are on the way to characterize all these abnormalities on the cellular and subcellular level.
- Since endothelial nitric oxide synthase (eNOS) is localized to caveolae, which can regulate its activity, recent studies have established the role of caveolar scaffolding protein, caveolin-1, in the modulation of nitric oxide synthase function. These studies are currently expanded to examine the role played by caveolin-1 and eNOS in chronic kidney disease.
- The above studies have branched out into the areas of diabetic vascular complications and pathogenesis of atherosclerotic vascular lesions, especially in patients with renal failure.
- We have established a novel mechanism of endothelial cell senescence in diabetes – premature senescence, and identified pharmacologic interventions capable of preventing and reversing senescent phenotype. Furthermore, recent data demonstrated that endothelial progenitor cells become functionally incompetent under these conditions.
- In parallel with these investigations, a clinical study into the early diagnosis of endothelial dysfunction in the dialysis patients, as assessed with laser Doppler flowmetry, are in progress.
- Yet another clinical study involves a proteomics approaches to identify diagnostic markers of renal allograft rejection. This work utilizes analysis of urine samples obtained from kidney transplant recipients.