The Missing Link: Studying the Alternative TGF-β Pathway Provides a Unifying Theory for Different Components of Diabetic Nephropathy

Diabetic nephropathy (DN) contributes to nearly 50% of chronic kidney disease and end-stage renal disease cases in the United States (1). Despite clinical trials that have affirmed the importance of glycemic control and the provision of inhibitors of the renin-angiotensin-aldosterone system for slowing progression of DN, the burden of disease continues to increase (2). Therefore further mechanistic studies are needed to understand the pathogenesis of DN. One of the earliest histologic changes in glomeruli from patients with DN is mesangial extracellular matrix (ECM) deposition (3). Ultrastructural studies also demonstrate increased glomerular basement membrane (GBM) thickness and podocyte foot process effacement (3). These lesions are associated with the development of albuminuria, but three fundamental questions remain: 1) Although transforming growth factor (TGF)-b signaling is an important mediator of these early lesions, why does treatment with an anti-TGF-b neutralizing antibody not reduce albuminuria (4)? 2) What is the contribution of each glomerular cell type to these lesions and to albuminuria? 3) What is the role of albuminuria in mediating further glomerular and tubular damage in DN? The article by Fan et al. (5) in this issue of Diabetes represents an important step forward in addressing these gaps in our knowledge of DN. How TGF-b induces albuminuria has been debated for more than a decade. In a now classic article, Ziyadeh et al. (4) demonstrated that reducing TGF-b bioavailability by administration of a neutralizing anti-TGF-b antibody in db/db mice decreased mesangial ECM expansion and progressive renal disease but did not reduce albuminuria. TGF-b signaling can be separated into the canonical pathway, mediated through Smad2 and Smad3, and the alternative pathway through Smad1 and Smad5 (6). Genetic deletion of Smad3 in mice reduces ECM deposition and GBM thickening but does not reduce albuminuria (7). By contrast, Chen et al. (8) demonstrated that gene delivery of Smad7, an inhibitor of both canonical and alternative TGF-b signaling (6,9), significantly reduces ECM deposition, GBM thickness, and albuminuria, suggesting TGF-b could contribute to albuminuria in DN. However, none of these articles specifically investigated the activation of the TGF-b alternative pathway. Fan et al. (5) studied the role of TGF-b alternative signaling in DN. Using knockout (KO) mice, they deleted BAMBI (BMP, activin, membrane-bound inhibitor), an endogenous antagonist of the TGF-b alternative pathway (10). When they induced diabetes in these BAMBI KO mice, activation of the alternative pathway caused podocyte foot process effacement and albuminuria but not ECM deposition or increased GBM thickness, suggesting TGF-b canonical and alternative pathways promote different components of the pathogenesis of DN (Fig. 1). A second strategy to specifically inhibit the TGF-b alternative signaling pathway is necessary to validate these results, for example, deletion of the Smad1 or Smad5 gene in diabetic mice. These results shed light on the debate of how TGF-b activation induces albuminuria and suggest several possibilities for why anti-TGF-b therapy did not reduce albuminuria. Perhaps antibody therapy preferentially inhibited the canonical pathway, or the alternative pathway is activated by decreased BAMBI expression. Moreover, since decreased BAMBI expression was observed in kidneys from both humans and mice with DN, activation of the alternative pathway may represent a modifier in the presentation of chronic kidney disease in DN with or without albuminuria (12). TGF-b also contributes to leukocyte kidney accumulation and to the epithelial-to-mesenchymal transition in DN (9,13),