Tubular hypertrophy due to work load induced by furosemide is associated with increases of IGF-1 and IGFBP-1.
We have examined the expression of insulin-like growth factor 1 (IGF-1), IGF binding protein-1 (IGFBP-1), and IGF binding protein-3 (IGFBP-3) in the rat distal nephron during increased cell work load and hypertrophy, induced by the diuretic, furosemide. Furosemide was given for six days to increase distal sodium delivery and uptake. To mitigate salt loss, the animals drank 0.8% NaCl and 0.1% KCl. Control rats were infused with vehicle (0.9% saline) and drank tap water. Furosemide increased urinary volume (13-fold) and sodium excretion (eightfold), and decreased urine osmolarity (fourfold). By immunocytochemistry, staining for IGF-1 and IGFBP-1 was markedly increased in distal convoluted tubules and cortical collecting ducts; both segments also underwent hypertrophy. Increased staining for the peptides was evident early (1 hr, 18 hr) after furosemide, prior to hypertrophy of cells. Whereas transcripts of IGF-1 and IGFBP-3 mRNA showed little or no increase in extracts from furosemide-treated kidney cortices, IGFBP-1 mRNA was increased threefold 18 hours after furosemide. Alterations of IGF-1 and IGFBP-1 were independent of changes in plasma aldosterone, glucocorticoids or arginine vasopressin. That IGFBP-1 mRNA increased threefold without significant changes in IGF-1 mRNA suggests that hypertrophic stimuli might initially induce the synthesis of IGF binding protein followed by the trapping of extracellular IGF-1. The present study raises the possibility of IGF-1 and IGFBP-1 being involved in processes that lead to tubular hypertrophy. IGFBP-1 may regulate these effects by binding to and interaction with IGF-1.
Kobayashi
S
S
Department of Pathology, University of Texas Health Science Center at San Antonio, USA.
Clemmons
D R
DR
Nogami
H
H
Roy
A K
AK
Venkatachalam
M A
MA
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005665:Furosemide / Q000494:pharmacology*; D006984:Hypertrophy / Q000378:metabolism; D007150:Immunohistochemistry; D018970:Insulin-Like Growth Factor Binding Protein 1; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D016526:Workload
D002352:Carrier Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D005665:Furosemide