Endothelin converting enzyme inhibition attenuates early albuminuria and late renal failure in streptozotocin induced diabetic mice

It has recently been established that a high salt diet leads to sodium storage within the skin of rats and mice. This increase in sodium in the highly vascularized skin results in macrophage infiltration and lymphangiogenesis. While dysfunction in this process has been implicated in salt sensitive hypertension, the mechanisms are poorly understood. Because vascular endothelin-1 (ET-1) is upregulated in response to a high salt diet or hypertonicity, and is a potent chemoattractant, we hypothesized that endothelial derived ET-1 mediates infiltration of immune cells into the skin during chronic high salt intake, thereby allowing sodium clearance from the skin and preventing accumulation. Our data indicate that increasing extracellular concentration of human endothelial cells by 40 mOsm with NaCl, similar to what is seen in the interstitial space of rats placed on a high salt diet, leads to a 50% increase in ET-1 production, a mechanism likely mediated by TonEBP. Furthermore, in response to one week of high salt diet, skin Na/water ratio was elevated in vascular endothelial cell ET-1 knockout mice compared to wild type mice (0.112 ± 0.007 vs. 0.096 ± 0.004 mmol/ml). These data suggest a critical role for ET-1 in preventing the accumulation of sodium in the skin during a high salt intake, an emerging mechanism of the body's ability to buffer blood pressure changes in response to increases in sodium intake.