Mechanisms of insulin-like growth factor-I-induced accelerated recovery in experimental ischemic acute renal failure.
Exogenous administration of recombinant human insulin-like growth factor I (rhIGF-I) to normal rats or humans increases renal blood flow and glomerular filtration rate (GFR). In rats with ischemic acute renal failure (iARF) the peptide accelerates the recovery of renal function and tubular integrity. These latter effects may be caused by renal hemodynamic actions of IGF-I or may result from direct actions of IGF-I on injured tubular cells. To examine this hypothesis, in vivo studies were performed in rats with iARF and in vitro experiments were conducted using a model of anoxia/reoxygenation injury in primary cultures of rat proximal tubular cells. In rats with iARF, IGF-I ameliorates the rise in serum creatinine, improves GFR, increases the rate of bromodeoxyuridine (BrdU) incorporation and the mitosis score, and reduces the number of apoptotic bodies. In acutely injured proximal tubular cells, IGF-I receptor mRNA levels decrease, but the remaining receptors are functional as indicated by ligand-induced phosphorylation of the IGF-I receptor beta-subunit. In anoxia/reoxygenation-injured cells, exogenous rhIGF-I improves ATP repletion, increases 3H-thymidine and BrdU incorporation and reduces the incidence of apoptosis as determined by the TUNEL method. We conclude that rhIGF-I accelerates the recovery of renal function in rats with iARF probably through hemodynamic effects, but in addition through direct metabolic, mitogenic and antiapoptotic actions on injured tubules.
Hirschberg
R
R
Division of Nephrology and Hypertension, Harbor-UCLA Medical Center and UCLA, Torrance, Calif 90509, USA. rhirschbe@aol.com
Ding
H
H
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005919:Glomerular Filtration Rate; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D007511:Ischemia / Q000188:drug therapy*; D007668:Kidney / Q000098:blood supply* / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use
D012333:RNA, Messenger; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase