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 because of reduced food intake, depressed growth hormone secretion, and low serum insulin-like growth factor-I (IGF-I) levels. Paradoxically, in the rat kidney, protein synthesis increases, cathepsin B and L activities decline, protein degradation falls, and the kidneys enlarge. Because IGF-I has been implicated as a cause of renal hypertrophy in a variety of conditions, we examined whether IGF-I could be playing a role in the renal hypertrophy of acidosis. Rats were gavaged with NH4Cl or water for 4 days. Water-gavaged rats 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 and IGF-I mRNA levels did not differ between the groups, but kidney IGF-I protein levels were significantly higher in the acidotic rats. After 4 days the kidneys of the acidotic rats were significantly larger than the kidneys in both control groups but the renal IGF-I levels did not differ between the groups. It is notable that renal cathepsin B and L mRNA levels were reduced by 30% to 50% at both times. Thus the transient increase in renal IGF-I protein levels in acidosis, before the onset of hypertrophy, suggests that IGF-I may play a role in initiating kidney growth. Furthermore, it appears that reduced cathepsin B and L gene expression is a cause of the low renal cathepsin activity seen in acidosis. This likely contributes to the depressed renal proteolysis caused by acidosis.