Effects of Increased Renal Tubular Vascular Endothelial Growth Factor (VEGF) on Fibrosis, Cyst Formation, and Glomerular Disease

Samy Hakroush^*, Marcus J. Moeller, Franziska Theilig, Brigitte Kaissling, Tjeerd P. Sijmonsma^¶, Manfred Jugold^||, Ann L. Akeson^**, Milena Traykova-Brauch^¶, Hiltraud Hosser^*, Brunhilde Hähnel^*, Hermann-Josef Gröne^¶, Robert Koesters and Wilhelm Kriz^*

From the Centrum für Biomedizin und Medizintechnik Mannheim,^* Anatomy and Developmental Biology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; the Division of Nephrology, Rheinisch-Westfaelische Technische Hochschule, Aachen, Germany; the Department of Anatomy, Charité, Berlin, Germany; the Department of Anatomy, University of Zürich, Zürich, Switzerland; the Department of Cellular and Molecular Pathology^¶ and the Division of Medical Physics in Radiology,|| German Cancer Research Center, Heidelberg, Germany; the Division of Pulmonary Biology,^*^* Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio; and the Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany

The role of vascular endothelial growth factor (VEGF) in renalfibrosis, tubular cyst formation, and glomerular diseases isincompletely understood. We studied a new conditional transgenicmouse system [Pax8-rtTA/(tetO)₇VEGF], which allows increasedtubular VEGF production in adult mice. The following pathologywas observed. The interstitial changes consisted of a ubiquitousproliferation of peritubular capillaries and fibroblasts, followedby deposition of matrix leading to a unique kind of fibrosis,ie, healthy tubules amid a capillary-rich dense fibrotic tissue.In tubular segments with high expression of VEGF, cysts developedthat were surrounded by a dense network of peritubular capillaries.The glomerular effects consisted of a proliferative enlargementof glomerular capillaries, followed by mesangial proliferation.This resulted in enlarged glomeruli with loss of the characteristiclobular structure. Capillaries became randomly embedded intomesangial nodules, losing their filtration surface. Serum VEGFlevels were increased, whereas endogenous VEGF production bypodocytes was down-regulated. Taken together, this study showsthat systemic VEGF interferes with the intraglomerular cross-talkbetween podocytes and the endocapillary compartment. It suppressesVEGF secretion by podocytes but cannot compensate for the deficit.VEGF from podocytes induces a directional effect, attractingthe capillaries to the lobular surface, a relevant mechanismto optimize filtration surface. Systemic VEGF lacks this effect,leading to severe deterioration in glomerular architecture,similar to that seen in diabetic nephropathy.