title: Expression of insulin-like growth factor-I and transforming growth factor-beta in hypokalemic nephropathy in the rat.
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-beta (TGF-beta) 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-beta 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-beta, 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-beta to hypertrophied nonhyperplastic nephron segments containing IGF-I raises the possibility that TGF-beta may be serving to convert the mitogenic action of IGF-I into a hypertrophic response in these segments. It is also conceivable 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.
authors.affiliation: Research Service Veterans Affairs Palo Alto Health Care System and Departments of Medicine and Pathology, Stanford University, Palo Alto, California, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tsao
authors.forename: J
authors.initials: J
authors.lastname: Fawcett
authors.forename: F C
authors.initials: FC
authors.lastname: Fervenza
authors.forename: F W
authors.initials: FW
authors.lastname: Hsu
authors.forename: P
authors.initials: P
authors.lastname: Huie
authors.forename: R K
authors.initials: RK
authors.lastname: Sibley
authors.forename: R
authors.initials: R
authors.lastname: Rabkin
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000235:genetics; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D007008:Hypokalemia / Q000097:blood / Q000150:complications*; D007150:Immunohistochemistry; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017451:Receptors, Somatomedin / Q000235:genetics; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D018970:Insulin-Like Growth Factor Binding Protein 1; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D011986:Receptors, Somatotropin; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; C534280:Ctsl protein, rat