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Acute and Chronic Renal Effects of Recombinant Human TGF-ß2 in the Rat

FRANCIS J. KELLY^*, SHARON ANDERSON^*, MICHELE M. THOMPSON^*, TERRY T. OYAMA^*, THOMAS M. KENNEFICK^*, CHRISTOPHER L. CORLESS, RICHARD J. ROMAN, LESLIE KURTZBERG^§, BRUCE M. PRATT^§ and STEVEN R. LEDBETTER^§

^* Division of Nephrology and Hypertension, Oregon Health Sciences University, Portland, Oregon
Medical and Pathology Services, Portland Veterans Administration Medical Center, Portland, Oregon
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
^§ Genzyme Corporation, Framingham, Massachusetts.

Correspondence to Dr. Steven R. Ledbetter, Genzyme Corporation, P.O. Box 9322, Framingham, MA 01701. Phone: 508-271-3636; Fax: 508-270-2088; E-mail: sledbetter{at}genzyme.com

Abstract. The expression of transforming growth factor-ß (TGF-ß) correlates with the incidence of renal glomerular and interstitial injury, however, nothing is known of the effect of these proteins on renal hemodynamics. This study examines the renal hemodynamic and morphologic effects of recombinant human TGF-ß2 in normal male Sprague Dawley rats. Acute infusion of TGF-ß2 (1.2 µg/kg per min) induced no hemodynamic changes, except for a modest though significant fall in mean arterial pressure. Administering TGF-ß2 at varying doses (20, 100, and 400 µg/kg) for 9 wk caused modest increases in systolic BP and proteinuria and minimal tubular interstitial fibrosis, however, renal hemodynamic end points were not significantly altered. TGF-ß2 (800 µg/kg) was also administered to volume-depleted rats for 7 consecutive days. In contrast to the findings in volume-replete animals, administration of TGF-ß2 to volume-depleted rats caused a marked reduction in GFR and medullary blood flow. Histologic fibrosis of the medullary vasa recta and cortical interstitium was seen, but glomeruli were unaffected. Thus, acute and short-term chronic TGF-ß2 administration did not induce major renal changes in the volume-replete state, however, TGF-ß2 combined with volume depletion caused medullary hypoperfusion and reduced GFR.

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