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

T. Tsao, J. Fawcett, Fernando Custodio Fervenza, F. W. Hsu, P. Huie, R. K. Sibley, R. Rabkin

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)96-105
Number of pages10
JournalKidney International
Volume59
Issue number1
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Transforming Growth Factors
Insulin-Like Growth Factor I
Kidney
Insulin-Like Growth Factor Binding Protein 1
Hypertrophy
Growth
Messenger RNA
Nephrons
Hyperplasia
Intercellular Signaling Peptides and Proteins
Fibrosis
Extremities
Potassium Deficiency
Diet
Insulin-Like Growth Factor Binding Proteins
Hypokalemia
Monocytes
Histology
Proteins
Eating

Keywords

  • Cathepsin
  • Fibrosis
  • Hypertrophy
  • Kidney disease
  • Potassium deficiency
  • Renal growth

ASJC Scopus subject areas

  • Nephrology

Cite this

Expression of insulin-like growth factor-I and transforming growth factor-β in hypokalemic nephropathy in the rat. / Tsao, T.; Fawcett, J.; Fervenza, Fernando Custodio; Hsu, F. W.; Huie, P.; Sibley, R. K.; Rabkin, R.

In: Kidney International, Vol. 59, No. 1, 2001, p. 96-105.

Research output: Contribution to journalArticle

Tsao, T. ; Fawcett, J. ; Fervenza, Fernando Custodio ; Hsu, F. W. ; Huie, P. ; Sibley, R. K. ; Rabkin, R. / Expression of insulin-like growth factor-I and transforming growth factor-β in hypokalemic nephropathy in the rat. In: Kidney International. 2001 ; Vol. 59, No. 1. pp. 96-105.
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AU - Fervenza, Fernando Custodio

AU - Hsu, F. W.

AU - Huie, P.

AU - Sibley, R. K.

AU - Rabkin, R.

PY - 2001

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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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