Robert Chevalier, M.D.

Robert Chevalier. M.D.I was born in Chicago, but was raised in Belgium, Italy and Switzerland. I returned to the United States, where I was awarded a B.S. in Zoology and M.D. from the University of Chicago. After pediatric residency at the University of North Carolina, I received my fellowship training in renal physiology in the laboratory of Dr. Carl Gottschalk, where I learned micropuncture techniques. This was followed by clinical pediatric nephrology fellowship at the University of Colorado. I then joined the faculty of the University of Virginia, where I established the Division of Pediatric Nephrology, and developed a laboratory supported by NIH funding for over 30 years. My initial research interests involved the study of renal sodium balance in early postnatal life, exploring the role of the renin-angiotensin system and atrial natriuretic peptide. This work involved the use of whole-animal physiology, isolated glomeruli, and cell culture studies. The latter were the result of a sabbatical year with Bernard Rossier at the University of Lausanne, Switzerland.

Congenital urinary tract malformations and heritable renal disorders account for the majority of cases of renal failure in infants and children. My laboratory has therefore focused on the physiologic and cellular response of the developing kidney to injury and/or loss of renal mass. For the past 25 years, I have retained a superb animal surgeon, Barbara Thornhill, and an equally expert microscopist, Michael Forbes, has served as a member of my research group for over 10 years. With these capable individuals running my laboratory, I was able to serve for 14 years as Chair of the Department of Pediatrics. In 2010, I stepped down from this position to return to my laboratory full-time. Last year, Carolina Galarreta joined our group, brining additional expertise in microscopic techniques.

Congenital urinary tract obstruction is the primary cause of pediatric chronic kidney disease, and we have explored the role of growth factors, cytokines, and signaling molecules in the adaptation of the developing kidney to unilateral ureteral obstruction (UUO). These include angiotensin, epidermal growth factor, insulin-like growth factor-1, transforming growth factor-β, vascular endothelial growth factor, clusterin and nitric oxide synthase. In response to advances in understanding the regulation of cell survival and cell death, additional studies have addressed the role of adenosine, ceramide, Bcl-2, BAD, selectins, connexins, ICAM-1, and osteopontin.

In the past five years, our attention has turned to an underappreciated pathway to nephron loss: the formation of atubular glomeruli and aglomerular tubules. Although originally described by Oliver and others using microdissection techniques in the 1930s, and by Marcussen using serial sectioning of individual nephrons in the 1990s, the phenomenon was not pursued due to the labor-intensive nature of these techniques. Instead, over the past decade most studies have been directed at renal interstitial fibrosis as the final common pathway of progressive renal injury, with chronic UUO serving as the primary animal model. Our observation of spontaneous formation of atubular glomeruli in mice with targeted deletion of endothelial nitric oxide synthase (eNOS) and in wild-type mice subjected to UUO has shifted our attention from the renal interstitium to the proximal tubule as the central target of acute and chronic renal injury. Using immunohistochemistry and detailed morphometric analysis, we have demonstrated rapid destruction of 60% of proximal tubular mass in the obstructed kidney of adult mice subjected to UUO, a process associated with oxidant stress, mitochondrial loss, and cell death by autophagy, apoptosis, and necrosis. This process occurs also in neonatal mice following UUO, but only after completion of nephron maturation: a 2-week delay. In collaboration with Jared Grantham in Kansas, we are now investigating mouse models of polycystic kidney disease (cpk and pcy) to test the hypothesis that tubular obstruction by cyst formation leads to proximal tubular injury and atubular glomeruli.

To explore novel therapies for congenital renal disease, we are currently investigating the effects on proximal tubular injury of antioxidants targeted to mitochondria (mitoquinone and hemigramicidin-TEMPO conjugate) in models of UUO. In collaboration with Corinne Antignac in Paris, we are studying the response to these agents in a newly developed model of nephropathic cystinosis, a rare inherited disorder of cystine transport resulting in proximal tubular injury. It is likely that oxidant-mediated proximal tubular injury is a key mechanism for progression of congenital renal disorders, with significant implications for chronic kidney disease in adulthood.