Increased mesangial collagen expression and deposition occurs in response to chronic progressive renal injury. Regulation of collagen metabolism is dependent on the heterodimeric transmembrane receptors for extracellular matrix (ECM) components, integrins. Integrin alpha1-beta1, one of the. major collagen binding receptors in this family, is highly expressed in the renal glomerulus. This receptor senses the level of extracellular collagen and negatively regulates its endogenous synthesis. Consistent with this observation, we have shown that cells derived from integrin alpha1-null mice fail to downregulate collagen synthesis when cultured in three-dimensional collagen gels. As ECM metabolism, particularly collagen, is a key component in the development of glomerulosclerosis, we hypothesize that the collagen receptor, integrin alpha1-beta1, plays a pivotal role in the modulation of glomerulosclerosis and ECM deposition following glomerular injury. To test our hypothesis we will 1) determine whether integrin alpha1-null mice develop increased and more severe glomerulosclerosis compared to their wild type counterparts in response to glomerular injury. Glomerular injury in wild type and integrin alpha1-null mice will be induced with la) intraperitoneal injection of antibodies raised against either whole glomeruli or some of its cellular components; 1b) intravenous injection of Adriamycin; 1c) partial renal ablation and 1d) intraperitoneal injection of streptozotocin to induce diabetes. This study will enable us to determine whether integrin alpha1-beta1 plays a direct role in the control of collagen synthesis, deposition and consequent glomerulosclerosis and to assess the suitability of different injury models to dissect alpha1-mediated molecular pathways that regulate collagen synthesis in glomerular injury. Identification of major players involved in the control of collagen synthesis will help us to develop in vivo strategies to prevent end stage renal disease.
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