TY - JOUR
T1 - Expression of insulin-like growth factor-I and transforming growth factor-β in hypokalemic nephropathy in the rat
AU - Tsao, Tanny
AU - Fawcett, Janet
AU - Fervenza, Fernando C.
AU - Hsu, Fay W.
AU - Huie, Phillip
AU - Sibley, Richard K.
AU - Rabkin, Ralph
N1 - Funding Information:
This study was supported by the Research service of the Department of Veterans Affairs and the American Heart Association Western States Affiliates. Dr. F. Fervenza was supported by funds from the Satellite Dialysis Fund of Northern California.
PY - 2001/1
Y1 - 2001/1
N2 - Background. Potassium deficiency (KD) in the rat retards body growth but stimulates renal enlargement caused by cellular hypertrophy and hyperplasia, which is most marked in the outer medulla. If hypokalemia persists, interstitial 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 transforming growth factor-β (TGF-β) promotes cellular hypertrophy and fibrosis, we examined the renal expression of these growth factors in prolonged 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 in whole kidney and protein expression localized by immunohistochemistry. Results. KD rats weighed less than pair-fed controls, while the kidneys were 49% larger. Their serum IGF-I and kidney IGF-I protein levels were depressed, as were their IGF-I mRNA levels in liver, kidney, and muscle. These changes can largely be attributed to decreased food intake. In contrast, kidney IGF binding protein-1 (IGFBP-1) mRNA and TGF-β mRNA levels were increased 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 interstitium. Both nephron segments immunostained strongly for IGF-I and IGFBP-1, but only the nonhyperplastic enlarged thick ascending Henle limb cells immunostained for TGF-β, which was strongly positive. Prominent interstitial infiltrates 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 through local trapping of IGF-I by the overexpressed IGFBP-1, which together with IGF-I can promote renal growth. The selective localization of TGF-β to hypertrophied nonhyperplastic nephron segments containing IGF-I raises the possibility that TGF-β may be serving to convert the mitogenic action of IGF-I into a hypertrophic response in these segments. It is also conceivable that TGF-β may be a cause of the tubulointerstitial infiltrate. Finally, the low circulating IGF-I levels likely contribute to the impaired body growth.
AB - Background. Potassium deficiency (KD) in the rat retards body growth but stimulates renal enlargement caused by cellular hypertrophy and hyperplasia, which is most marked in the outer medulla. If hypokalemia persists, interstitial 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 transforming growth factor-β (TGF-β) promotes cellular hypertrophy and fibrosis, we examined the renal expression of these growth factors in prolonged 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 in whole kidney and protein expression localized by immunohistochemistry. Results. KD rats weighed less than pair-fed controls, while the kidneys were 49% larger. Their serum IGF-I and kidney IGF-I protein levels were depressed, as were their IGF-I mRNA levels in liver, kidney, and muscle. These changes can largely be attributed to decreased food intake. In contrast, kidney IGF binding protein-1 (IGFBP-1) mRNA and TGF-β mRNA levels were increased 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 interstitium. Both nephron segments immunostained strongly for IGF-I and IGFBP-1, but only the nonhyperplastic enlarged thick ascending Henle limb cells immunostained for TGF-β, which was strongly positive. Prominent interstitial infiltrates 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 through local trapping of IGF-I by the overexpressed IGFBP-1, which together with IGF-I can promote renal growth. The selective localization of TGF-β to hypertrophied nonhyperplastic nephron segments containing IGF-I raises the possibility that TGF-β may be serving to convert the mitogenic action of IGF-I into a hypertrophic response in these segments. It is also conceivable that TGF-β may be a cause of the tubulointerstitial infiltrate. Finally, the low circulating IGF-I levels likely contribute to the impaired body growth.
KW - Cathepsin
KW - Fibrosis
KW - Hypertrophy
KW - Kidney disease
KW - Potassium deficiency
KW - Renal growth
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U2 - 10.1046/j.1523-1755.2001.00470.x
DO - 10.1046/j.1523-1755.2001.00470.x
M3 - Article
C2 - 11135062
AN - SCOPUS:0035175688
SN - 0085-2538
VL - 59
SP - 96
EP - 105
JO - Kidney international
JF - Kidney international
IS - 1
ER -