Rats with 5/6 nephrectomy have metabolic acidosis with a progressive decline in the glomerular filtration rate (GFR) ameliorated by endothelin and aldosterone antagonists and by dietary alkali. Interestingly, rats with 2/3 nephrectomy have no metabolic acidosis yet have a progressive GFR decline induced by acid retention and ameliorated by dietary alkali. Because patients without metabolic acidosis but with a moderately reduced GFR have a progressive GFR decline, ameliorated by oral sodium bicarbonate, we used rats with 2/3 nephrectomy to model these patients. Kidney acid content, endothelin-1, and aldosterone (measured by microdialysis) were higher in the rats with 2/3 nephrectomy than those with a sham operation despite no differences in plasma acid-base parameters. The GFR of the former but not the latter was lower at 25 than at 1 week after nephrectomy. Endothelin and aldosterone antagonism improved the preservation of GFR; however, this remained lower at week 24 than at week 1. By contrast, the GFR at weeks 24 and 1 was not different if the rats were given dietary alkali to normalize the kidney acid content. Antagonist of endothelin and aldosterone yielded no added GFR benefit. Thus, our study shows that (1) the decline in GFR in 2/3 nephrectomy is mediated by acid retention-induced kidney endothelin and aldosterone production; (2) receptor antagonism and dietary alkali are not additive; and (3) dietary alkali better preserves GFR than both endothelin and aldosterone receptor antagonism.