Renal endothelin gene expression is increased in remnant kidney and correlates with disease progression

Abstract

We previously demonstrated that urinary endothelin excretion is increased in rats with extensive renal mass reduction, a model of progressive renal disease. Here we explored whether the increased urinary endothelin in this model were due to induction of renal pre-pro-endothelin-1 gene and whether changes in endothelin synthetic pathway correlated with the development of glomerulosclerosis. Four groups of rats with renal mass reduction and four groups of sham-operated control rats were studied 7, 30, 60 and 120 days after the surgical procedure. Urinary protein excretion in renal mass ablation animals did not differ from controls at seven days, but was already significantly elevated (P < 0.01) 30 days after surgery. Then proteinuria progressively increased in rats with remnant kidney at values above 400 mg/day at day 120. Serum creatinine concentration also progressively increased with time in renal mass ablation rats, unlike sham-operated animals, and values were significantly different (P < 0.01) at each of the points considered. Rats with renal mass reduction, unlike sham-operated animals, developed focal glomerulosclerosis that affected 8% of glomeruli at day 30, and 24% of glomeruli at day 120. Seven days after renal mass reduction renal pre-proendothelin-1 (pre-pro ET) mRNA was comparable to that of shamoperated rats, while a 2.5-, 5- and fourfold increase in 2.3 Kb preproET-1 transcript was observed at 30, 60 and 120 days, respectively. Urinary excretion of endothelin was significantly elevated (P < 0.01) in rats with renal mass reduction with respect to sham-operated rats, starting from 30 days after surgery and increased further thereafter. A significant correlation (P < 0.01) was found between urinary endothelin-1 excretion values and the percent of glomeruli affected by glomerulosclerosis. We conclude that the progression of renal disease after surgical ablation of renal mass is associated with an increased renal endothelin-1 gene expression together with an excessive urinary excretion of the corresponding protein. It is speculated that endothelin may mediate glomerular structural abnormalities associated with the progression of renal disease in this model.