Different roles for TGF-b and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy Fuad N. Ziyadeh * Departments of Internal Medicine and Biochemistry, Faculty of Medicine, American University of Beirut, Bliss Street, Beirut, Lebanon 1. Introduction Transforming growth factor-beta (TGF-b) plays a pivotal role in mediating the hypertrophic and fibrotic/sclerotic manifes- tations of diabetic nephropathy [1]. Many investigations in cell culture systems [2–4], experimental animal models [5], and human studies [6] performed over the past 15 years have shown that renal TGF-b1 production is increased during the development of diabetic kidney disease. 2. Mechanisms Multiple mediators in the diabetic milieu, be they hemody- namic or metabolic, including oxidative stress and none- nzymatic adducts of the amadori [7] or advanced glycating types [8], converge to up-regulate TGF-b and its signaling type II receptor in the kidney [9,10]. The uptake of glucose via Glut1 and its subsequent intracellular metabolism via different pathways leads to TGF-b1 overproduction [11], diabetes research and clinical practice 82s (2008) s38–s41 article info Published on line 7 October 2008 Keywords: Mesangial cells Extracellular matrix Podocytes Angiotensin II Albuminuria abstract Hemodynamic stress in concert with metabolic pathways that are activated by hypergly- cemia, glycated proteins, and oxidative stress induce a host of growth factors in the kidney. The fibrogenic cytokine transforming growth factor-beta (TGF-b), through its Smad3 signal- ing pathway, is the etiologic agent of renal hypertrophy and the accumulation of mesangial extracellular matrix components in diabetes. Neutralizing anti-TGF-b antibodies, antisense TGF-b1 oligodeoxynucleotides or knocking off the Smad3 gene prevent and/or reverse the hypertrophic and profibrotic effects of the diabetic state in mice. However, there is limited evidence to support a role for TGF-b in the development of albuminuria. Podocyte-derived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor whose expression is also increased in animal models of diabetic kidney disease, appears to act in a novel autocrine signaling mode to induce the podocytopathy of diabetes, especially the genesis of albuminuria. Future strategies for therapy of diabetic nephropathy may therefore need to involve interception of both the TGF-b and the VEGF signaling pathways to counter the matrix accumulation and to improve the albuminuria. Interception of the renin– angiotensin system may achieve this goal but other novel strategies will need to be developed that would be more efficacious. However, a note of caution should be raised not to lower the heightened activities of these two signaling pathways much below normal levels because a basal activity for each is essential for the optimal homeostasis of glomerular cells. # 2008 Published by Elsevier Ireland Ltd. * Tel.: +961 1 350000x5353; fax: +961 1 744464. E-mail address: ziyadehf@yahoo.com. available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/diabres 0168-8227/$ – see front matter # 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.diabres.2008.09.016