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Prevention of Acute Ischemic Renal Failure by Targeted Delivery of Growth Factors to the Proximal Tubule in Transgenic Mice: The Efficacy of Parathyroid Hormone-Related Protein and Hepatocyte Growth Factor

Nathalie M. Fiaschi-Taesch^*, Soledad Santos^*,, Vasumathi Reddy^*, Scott K. Van Why, William F. Philbrick, Arantxa Ortega, Pedro Esbrit, John J. Orloff and Adolfo Garcia-Ocaña^*

*Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pediatrics and Division of Endocrinology, Yale University, New Haven, Connecticut; and Bone and Mineral Metabolism Laboratory, Research Unit, Fundación Jiménez Díaz, Madrid, Spain

Correspondence to Dr. Adolfo Garcia-Ocaña, BST E-1156, University of Pittsburgh, 3550 Terrace St, Pittsburgh, PA 15213. Phone: 412-648-9770; Fax: 412-648-3290;

ABSTRACT. Treatment of acute renal failure (ARF) would be enhanced by identification of factors that accelerate renal recovery from injury. Parathyroid hormone-related protein (PTHrP) and hepatocyte growth factor (HGF) have been shown to stimulate proliferation in proximal nephron-derived cells. For studying the pathophysiologic roles and therapeutic potential of these two factors in ARF, transgenic mice overexpressing PTHrP or HGF in the proximal tubule under the direction of the -glutamyl transpeptidase-I promoter were developed. These mice display (1) abundant expression of the respective transgenes in the kidney; (2) similar PTH type I receptor and HGF receptor (c-met) expression levels in the proximal tubule compared with control littermates; and (3) normal renal morphology, function, and tubule cell proliferation under basal conditions. However, in contrast to control mice, when acute ischemic renal injury was induced, renal function rapidly and dramatically recovered in HGF-overexpressing mice. In addition, 48 h after ischemia, HGF-overexpressing transgenic mice displayed a fourfold increase in tubule cell proliferation and a threefold decrease in apoptotic tubule cell death compared with control mice. In contrast, PTHrP-overexpressing mice responded to either ischemic or folic acid-induced renal damage similarly to control mice. These studies demonstrate that overexpression of PTHrP in the proximal nephron of mice does not seem to provide protection against acute renal injury. In marked contrast, HGF overexpression results in dramatic protection from ischemia-induced ARF, without inducing any apparent alteration in the physiology of the kidney under normal conditions. These studies suggest that HGF, when targeted specifically to the proximal tubule, may have therapeutic potential in providing protection against ischemia-induced renal failure. E-mail: ocana@msx.dept-med.pitt.edu

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