Bioactivity of glomerular ultrafiltrate during heavy proteinuria may contribute to renal tubulo-interstitial lesions: evidence for a role for insulin-like growth factor I.
Year: 1996
Type: article
Abstract: Clinical and experimental data have indicated that heavy proteinuria in renal glomerular diseases is associated with the formation of tubulo-interstitial fibrosis and contributes to the progression of renal failure.Albumin in glomerular ultrafiltrate does not appear to cause this sequelae, rather than compounds that are associated with ultrafiltered plasma proteins.One such protein-bound factor could be insulin-like growth factor I (IGF-I).The present studies show that in nephrotic rats, IGF-I is ultrafiltered in conjunction with IGF-binding protein-2 and is present in proximal tubular fluid at 1.35 nM.Proximal tubular fluid from nephrotic rats autophosphorylates IGF-I receptors in cultured proximal tubular cells.Nephrotic, but not control, rat proximal tubular fluid increases the [ 3 H]thymidine incorporation in cultured tubular cells, and neutralizing IGF-I-receptor antibodies partially inhibit this activity.Incubation of cultured proximal tubular cells with an extract that was prepared from nephrotic rat urine increases the secretion of collagen types I and IV.Secretion of the two collagens is in part ameliorated by neutralizing IGF-I-receptor antibody.In concert, these findings suggest that the IGF-I present in nephrotic rat tubular fluid is bioactive and may contribute to the development of tubulo-interstitial fibrosis in chronic nephrotic glomerular diseases.( J. Clin.Invest.1996.97: 116-124.)Key words: insulin-like growth factor I • insulinlike growth factor-binding proteins • glomerular ultrafiltrate • interstitial fibrosis • nephrotic syndrome Methods In vivo studiesThe nephrotic syndrome was induced in male Munich Wistar rats (200-250 g body wt; Simonson, Gilroy, CA) with a single intravenous injection of Doxorubicin-HCl (Adriamycin; Cetus Corp., Emeryville, CA), 4 mg/kg.Adriamycin has been shown to induce a minimalchange diseaselike glomerular lesion in rats that is associated with heavy proteinuria, hypoalbuminemia, and hypercholesterolemia (18).These findings are comparable with the more clearly defined ne-
DOI: 10.1172/jci118755
Author: R Hirschberg
Institution: Harbor–UCLA Medical Center
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: American Heart Association
OpenAlex ID: W1973460641