Smooth Muscle Stem Cells in Rapidly Aging Glomeruli

Striker, Gary

Abstract

Diabetic nephropathy is a severe complication in aging patients with type 2 diabetes mellitus. We hypothesize that diabetic nephropathy results from a phenotypic alteration in bone marrow-derived mesangial stem cells. We propose to test this hypothesis, using diabetic mice with a permissive (sclerosis-prone) background, since nephropathy only develops in such strains. While normal aging results in slowly developing nephropathy in these strains, it is sharply accelerated by diabetes mellitus. Diabetes causes a stable phenotypic switch in glomerular mesangial cells, characterized by increased cell turnover and increased extracellular matrix deposition. We postulate that the defect likely has a stem cell origin, since the lesions are diffuse, are characterized by a uniform and stable change in mesangial cell phenotype, are common between several sclerosis-prone mice strains, and are present in type 2 diabetic patients. Furthermore, the commonality of this change suggests that it is a conserved stem cell response and possibly limited to a small number of defects. We showed that a glomerular macrophage stem cells were bone marrow-derived.
Three specific aims are proposed for this pilot application: 1) Establish that mesangial stem cells in the rapidly aging kidney of sclerosis-prone mice are bone marrow-derived. 2) Determine whether transplantation of bone marrow-derived stem cells from sclerosis-prone mice with rapidly aging kidneys will repopulate the mesangial region of young sclerosis-prone mice and induce an aging lesion. 3) Determine whether transplantation of bone marrow derived stem cells from young sclerosis-resistant animals, into sclerosis-prone animals with rapidly aging kidneys will repopulate the mesangial regions and ameliorate the renal lesions.