Endothelin Antagonists and Renal Protection

Proteinuric nephropathies either of diabetic or nondiabetic origin tend to develop renal structural damage associated with progressive renal function decline over time. In proteinuric glomerular disease excessive protein reabsorption by proximal tubular epithelial cells modulates tubular cell function to the extent that cell growth and their phenotypic expression of growth factors and inflammatory chemokines and cytokines is upregulated. Recent evidence is available that renal tubular cells synthesize endothelins (ETs), a family of peptides with potent vasoconstrictor and proliferation properties, and that overloading these cells with proteins induces a dose-dependent increase in the synthesis and release of ET-1. This peptide, accumulating in the renal interstitium, eventually participates in activation of the sequence of events that leads to interstitial inflammation and ultimately renal scarring. Increased renal synthesis of ET-1 occurs in vivo as documented in several animal models of proteinuric progressive nephropathies, in which enhanced renal ET-1 gene expression as well as the excretion of the peptide in the urine correlated with the urinary protein excretion rate. Similarly, in patients with chronic renal disease an association has been found between increased urinary excretion of ET-1 and renal damage. A strong argument in favor of ET-1 as a mediator of renal injury derives from preclinical studies with selective and non-selective ET receptor antagonists that have became available in the past few years. They block the effect of ET to their specific receptors called ET(A) and ET(B), and have been reported to have a renoprotective effect in several animal models of progressive renal disease, including in rats with remnant kidney or experimental diabetes as well as mice with lupus nephritis. The peptide nature of some of these compounds, which are currently appearing in the literature, may however hamper their future use in humans. Administration of nonpeptide ET receptor antagonists to humans would hopefully overcome this problem and possibly provide a new therapeutic approach for patients with renal disease who do not adequately respond to the currently available therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists.