Expression of insulin-like growth factor-I and transforming growth factor-beta in hypokalemic nephropathy in the rat

Background. Potassium deficiency (KD) in the rat retards body growth but st imulates renal enlargement caused by cellular hypertrophy and hyperplasia, which is most marked in the outer medulla. If hypokalemia persists, interst itial infiltrates appear and eventually fibrosis. Since early in KD insulin -like growth factor-I (IGF-I) levels in the kidney are elevated, suggesting that it may be an early mediator of the exaggerated renal growth, and as t ransforming growth factor-beta (TGF-beta) promotes cellular hypertrophy and fibrosis, we examined the renal expression of these growth factors in prol onged KD. Methods. Rats were given a K-deficient diet or were pair fed or ad libitum fed a K-replete diet for 21 days. Growth factor mRNA levels were measured i n whole kidney and protein expression localized by immunohistochemistry. Results. KD rats weighed less than pair-fed controls, while the kidneys wer e 49% larger. Their serum IGF-I and kidney IGF-I protein levels were depres sed, as were their IGF-I mRNA levels in liver, kidney, and muscle. These ch anges can largely be attributed to decreased food intake. In contrast, kidn ey IGF binding protein-1 (IGFBP-1) mRNA and TGF-beta mRNA levels were incre ased significantly. Histology of outer medulla revealed marked hypertrophy and adenomatous hyperplasia of the collecting ducts and hypertrophy of the thick ascending limbs of Henle with cellular infiltrates in the interstitiu m. Both nephron segments immunostained strongly for IGF-I and IGFBP-1, but only the nonhyperplastic enlarged thick ascending Henle limb cells immunost ained for TGF-beta, which was strongly positive. Prominent interstitial inf iltrates with ED1 immunostained monocytes/macrophages were present. Conclusions. These findings are consistent with a sustained role for IGF-I in promoting the exaggerated renal growth of KD and appear to be mediated t hrough local trapping of IGF-I by the overexpressed IGFBP-1, which together with IGF-I can promote renal growth. The selective localization of TGF-bet a to hypertrophied nonhyperplastic nephron segments containing IGF-I raises the possibility that TGF-beta may be serving to convert the mitogenic acti on of IGF-I into a hypertrophic response in these segments. It is also conc eivable that TGF-beta may be a cause of the tubulointerstitial infiltrate. Finally, the low circulating IGF-I levels likely contribute to the impaired body growth.