Date of Award

1-1-2004

Embargo Period

1-1-2004

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

Steven Rosenzweig

Second Advisor

Jerry G. Webb

Third Advisor

Edward Krug

Fourth Advisor

Thomas Walle

Fifth Advisor

Dhandapani Kuppuswamy

Abstract

Dysregulation of the insulin-like growth factor (IGF) system plays a key role in the hyperproliferative state seen in diabetic complications. Enhanced IGF-I activity plays a causal role in diabetic glomerulosclerosis (DG) by stimulating mesangial cell proliferation, secretion and hypertrophy. Other alterations of the IGF system may include increased IGF-I receptor (IGF-IR) and increased IGF binding protein (IGFBP) expression. The IGFBP family consists of six soluble binding proteins, IGFBP 1-6, which have higher affinities for the IGFs than the IGF-IR, resulting in blocking IGF access to the IGF-IR. Since the IGFBPs primarily function to inhibit IGF action, we hypothesize that overexpression of the IGF-IR will result in increased IGFBP secretion in an attempt to counteract the effects of IGF activation of the IGF-IR. In order to characterize the secretion of IGFBP-2, we have established stable mesangial cells (clone c5M1) expressing an approximate 3.5-fold increase in IGF-IR number compared to parental cells. IGFBP-2 secretion was quantified in conditioned medium from serum-starved parental and c5M1 cells. Our results indicate that c5M1 cells express a six-fold increase in IGFBP-2 secretion compared to parental cells. c5M1 cells also display a larger surface area and grow more rapidly. The addition of exogenous IGF-I increased IGFBP-2 secretion in parental and c5M1 cells but this increase was not significant. These results may reflect some of the clinical features of DG including mesangial cell hypertrophy and proliferation seen during the early clinical stage. The effect of IGF-IR overexpression on IGFBP-2 secretion may serve as a compensatory mechanism to block the effects of increased activation of the IGF-IR. These findings provide important insight into the contributions of each component of the IGF system to the complications of diabetes.

Rights

All rights reserved. Copyright is held by the author.

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