Abstract
Dietary sodium chloride (salt) has long been considered injurious to the kidney by promoting the development of glomerular and tubulointerstitial fibrosis. Endothelial cells throughout the vasculature and glomeruli respond to increased dietary salt intake with increased production of transforming growth factor-β (TGF-β) and nitric oxide. High-salt intake activates large-conductance, voltage- and calcium-activated potassium (BK(Ca)) channels in endothelial cells. Activation of BK(Ca) channels promotes signaling through proline-rich tyrosine kinase-2, cellular-sarcoma (c-Src), Akt (also known as protein kinase B), and mitogen-activated protein kinase pathways that lead to endothelial production of TGF-β and nitric oxide. TGF-β signaling is broadly accepted as a strong stimulator of renal fibrosis. The classic description of TGF-β signaling pathology in renal disease involves signaling through Smad proteins resulting in extracellular matrix deposition and fibrosis. Active TGF-β1 also causes fibrosis by inducing epithelial-mesenchymal transition and apoptosis. By enhancing TGF-β signaling, increased dietary salt intake leads to progressive renal failure from nephron loss and glomerular and tubulointerstitial fibrosis.