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Endothelial cell injury closely correlates with albuminuria in patients with DN ( 17). These results provide an intriguing hypothesis that TGF-β alternative signaling might contribute to podocytopathy and albuminuria through primary damage of the glomerular endothelial cell. ( 5) demonstrated that glomerular VEGFR2 is expressed only in endothelial cells, and activation of the TGF-β alternative signaling pathway decreases endothelial expression of VEGFR2. The information flowing in the neural channels including the brain stem (mostly automatic, effortless. According to Kammoun, financial decisions become financial acts when they pass the bottleneck in the upper brain stem below which all the motor neurons are available. ( 16) previously demonstrated endothelial injury in BAMBI KO mice. Neural cognitive and affective processes influence our financial decisions. ( 15) demonstrated that podocyte-secreted vascular endothelial growth factor (VEGF) maintains a normal glomerular filtration barrier by paracrine signaling through its receptor VEGF receptor 2 (VEGFR2) on glomerular cell types other than podocytes, but whether this mechanism contributes to DN is unknown. Many factors causing albuminuria in DN have been identified ( 14), but the contribution of each glomerular cell type (endothelial cells, mesangial cells, and podocytes) is unknown. Studying these end points in Smad3 KO and BAMBI KO mice will answer these questions. TGF-β also contributes to leukocyte kidney accumulation and to the epithelial-to-mesenchymal transition in DN ( 9, 13), but which signaling pathways are responsible is still unknown. 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). Perhaps antibody therapy preferentially inhibited the canonical pathway, or the alternative pathway is activated by decreased BAMBI expression. These results shed light on the debate of how TGF-β activation induces albuminuria and suggest several possibilities for why anti-TGF-β therapy did not reduce albuminuria.
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A second strategy to specifically inhibit the TGF-β alternative signaling pathway is necessary to validate these results, for example, deletion of the Smad1 or Smad5 gene in diabetic mice. 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-β canonical and alternative pathways promote different components of the pathogenesis of DN ( Fig. Using knockout (KO) mice, they deleted BAMBI (BMP, activin, membrane-bound inhibitor), an endogenous antagonist of the TGF-β alternative pathway ( 10). ( 5) studied the role of TGF-β alternative signaling in DN.