Molecular events during progression from microalbuminuria to diabetic nephropathy
Oliver Smithies   (Chapel Hill, NC)
Abstract The occurrence of microalbuminuria in diabetic individuals is a well established risk factor for subsequent progression to nephropathy. Interrupting or reversing this progression is the aim of clinicians who care for diabetic patients. Yet, at the subcellular and molecular levels, there is a clear gap in our understanding of this progression. I have two tools that put me in a unique position to fill this gap. The first tool is the superb and diverse collection of well-characterized diabetic mice developed by the AMDCC, some of which undergo the progression from microalbuminuria to diabetic nephropathy (DN). The second tool, developed by my group under an R21 grant, is a diverse collection of gold nanoparticles and fluorescent proteins, with molecular sizes covering the range of plasma proteins, which are directly visible by electron and confocal microscopy as they enter and traverse the kidney. Specific Aim 1 will take advantage of these tools to determine the degree to which the progression from microalbuminuria to overt albuminuria is the consequence of deterioration in the glomerular filtration barrier, as judged by changes in the ability of the glomerular basement membrane (GBM) to exclude molecules in a graded manner inversely related to their size. Specific Aim 2 will likewise determine the degree to which the progression is consequence of deterioration in tubular function, as judged by changes in the removal of macromolecules from the tubular fluid. We expect to obtain sufficient knowledge from our proposed pilot study to be able to assess the feasibility of applying the same procedures to evaluate the efficacy of new pharmaceutical interventions aimed at preventing or reversing the devastating progression of nephropathy that so frequently occurs in diabetics who develop microalbuminuria.