Role of Endothelin in the Development of Glomerulosclerosis

Enhanced filtered load of proteins in glomerular diseases (overload proteinuria) results in significant increase in the rate of proximal tubular uptake that is true for all proteins tested so far, including albumin. The excess concentration of absorbed proteins in lysosomes may itself lead to cellular damage by spillage of lysosomal enzymes to the cytosol. In vitro evidence is also available of functional alteration of these tubular cells, including upregulation of genes encoding for endothelin-1 (ET-1) and other inflammatory mediators, when they are overloaded in culture with proteins or lipoproteins. This could affect renal function and structure given the inflammatory, growth factor, and vasoactive properties of ET-1. Findings in several experimental models of proteinuric progressive nephropathies have indeed documented enhanced renal ET-1 gene expression and excretion of the peptide into the urine which correlated with proteinuria and the degree of glomerular and tubulointerstitial damage.