Effect of metabolic acidosis on the insulin-like growth factor-I system and cathepsins B and L gene expression in the kidney

Prolonged acidemia causes growth retardation and muscle wasting, in part be cause of reduced food intake, depressed growth hormone secretion, and low s erum insulin-like growth factor-I (IGF-l) levels. Paradoxically, in the rat kidney, protein synthesis increases, cathepsin B and L activities decline, protein degradation falls, and the kidneys enlarge. Because IGF-l has been implicated as a cause of renal hypertrophy in a variety of conditions, we examined whether IGF-l could be playing a role in the renal hypertrophy of acidosis. Rats were gavaged with NH4Cl or water for 4 days. Water-gavaged r ats either were pair-fed with the NH4Cl-loaded rats (pH 7.15) or were given free access to food and served as controls. After 2 days, kidney weight an d IGF-l mRNA levels did not differ between the groups, but kidney IGF-l pro tein levels were significantly higher in the acidotic rats. After 4 days th e kidneys of the acidotic rats were significantly larger than the kidneys i n both control groups but the renal IGF-l levels did not differ between the groups. It is notable that renal cathepsin B and L mRNA levels were reduce d by 30% to 50% at both times. Thus the transient increase in renal IGF-l p rotein levels in acidosis, before the onset of hypertrophy, suggests that I GF-l may play a role in initiating kidney growth. Furthermore, it appears t hat reduced cathepsin B and L gene expression is a cause of the low renal c athepsin activity seen in acidosis. This likely contributes to the depresse d renal proteolysis caused by acidosis.