Mesangial cell volume increases and proliferation correlate with the development of diabetic nephropathy. Metabolic alterations associated with diabetes, principally chronic hyperglycemia, are believed to produce cell inositol depletion which in turn is expected to influence cell phosphoinositide turnover, a signalling mechanism of proposed importance in cell function and proliferation, these effects may also be pertinent to mesangial cell changes associated with diabetes mellitus. More distal than signals in the chain of events leading to these changes may be the actin cytoskeletal system, believed important for cell shape, cell movement, cell volume and possibly cell proliferation. Recent data implicates phosphatidylinositol-4, 5-bisphosphate in the regulation of two key actin-modulating proteins, profilin and gelsolin, that latter also being influenced by micromolar calcium concentrations; calcium is also believed to activate cytoplasmic myosin by phosphorylation it though the medium of calmodulin and myosin kinases. Methods have also recently been developed for examining high affinity interactions between these regulatory proteins and actin, for quantifying the state of assembly of actin biochemically and for evaluating the three-dimensional architecture of actin in the cell. All of these assays can be done on small samples of cells or tissue. The investigators propose to examine effects of diabetes-associated metabolic perturbations such as hyperglycemia, inositol depletion, and aldose reductase inhibition on the state of actin assembly, associations between profilin and actin and gelsolin and actin, and the extent of myosin phosphorylation, first in blood cells in which the actin system has been more completely studied, and then in cultured mesangial cells. The three-dimensional architecture of actin filaments in control and experimentally diabetic mesangial cells will also be determined.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Greenfeld, Z; Stillman, I E; Brezis, M et al. (1997) Medullary injury in the ageing rat kidney: functional-morphometric correlations. Eur J Clin Invest 27:346-51
Stillman, I E; Brezis, M; Heyman, S N et al. (1994) Effects of salt depletion on the kidney: changes in medullary oxygenation and thick ascending limb size. J Am Soc Nephrol 4:1538-45
Brugnara, C; De Franceschi, L; Alper, S L (1993) Ca(2+)-activated K+ transport in erythrocytes. Comparison of binding and transport inhibition by scorpion toxins. J Biol Chem 268:8760-8
Heyman, S N; Stillman, I E; Brezis, M et al. (1993) Chronic amphotericin nephropathy: morphometric, electron microscopic, and functional studies. J Am Soc Nephrol 4:69-80
Heyman, S N; Brezis, M; Epstein, F H et al. (1992) Effect of glycine and hypertrophy on renal outer medullary hypoxic injury in ischemia reflow and contrast nephropathy. Am J Kidney Dis 19:578-86
Pacheco-Silva, A; Bastos, M G; Muggia, R A et al. (1992) Interleukin 2 receptor targeted fusion toxin (DAB486-IL-2) treatment blocks diabetogenic autoimmunity in non-obese diabetic mice. Eur J Immunol 22:697-702
Rauchman, M I; Wasserman, J C; Cohen, D M et al. (1992) Expression of GLUT-2 cDNA in human B lymphocytes: analysis of glucose transport using flow cytometry. Biochim Biophys Acta 1111:231-8
Heyman, S; Spokes, K; Rosen, S et al. (1992) Mechanism of glycine protection in hypoxic injury: analogies with glycine receptor. Kidney Int 42:41-5
Rosen, S; Epstein, F H; Brezis, M (1992) Determinants of intrarenal oxygenation: factors in acute renal failure. Ren Fail 14:321-5
Hallaq, H; Smith, T W; Leaf, A (1992) Modulation of dihydropyridine-sensitive calcium channels in heart cells by fish oil fatty acids. Proc Natl Acad Sci U S A 89:1760-4

Showing the most recent 10 out of 53 publications