MAP KINASE IN THE EVOLUTION OF GLOMERULOSCLEROSIS

University Of Wisconsin Madison, Madison WI

Investigators

Abstract

DESCRIPTION (adapted from the application) This R03 application corresponds to Dr. Bryan Becker's K08 award entitled "Properties of Proximal Tubule Angiotensin 11 Receptors," grant number DK02420. Glomeruli are elastic structures that can alter their volume in response to changes in intraglomerular pressure. But, their ability to distend and contract in response to intraglomerular pressure is a paradox. The characteristics that allow resident cells within glomeruli to respond to pressure changes across the glomerular bed also induce a variety of responses within these cells that set into motion extracellular matrix accumulation and glomerulosclerosis. Mesangial cells, positioned adjacent to the glomerular capillary basement membrane, are an important cell type involved in this process. Cell culture studies demonstrated that mesangial cells undergoing cyclical stretch/relaxation increased the synthesis and accumulation of extracellular matrix proteins and did so, in concert with activation of the renin-angiotensin system. We hypothesize that the MAP kinase signaling cascade is the site where the renin-angiotensin system and mechanical forces coincide to alter the glomerular interstitial scaffolding and replace functional renal mass with increasing amounts of collagen. By subjecting cultured mesangial cells to cyclical stretch/relaxation, we can examine whether this hypothesis is, in fact, true. We will assess the impact of angiotensin 11 (Ang 11) and stretch/relaxation-induced MAP-kinase activation on matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) mRNA expression and activity. Finally, we will evaluate additional MAP-kinase related signaling pathways that may be important for mesangial cell-initiated glomerulosclerosis. Ultimately, the experiments outlined in this proposal are designed to examine how mesangial cells make their first moves from an injury response to fibrosis in the context of a cell model that mimics mechanical stress invoked by fluctuations in intraglomerular pressure.