ALTERATIONS IN GLOMERULAR PROTEOGLYCAN METABOLISM IN EXPERIMENTAL NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Glomerular proteoglycans (PG) are important in modulating extracellula r matrix assembly and glomerular permselectivity. In the obese Zucker rat, an experimental model of non-insulin dependent diabetes mellitus, expansion of the mesangial matrix, and microalbuminuria occur before the development of overt renal disease. The in vivo incorporation of ( S-35)sulfate into glomerular PG in 12-wk-old obese Zucker rats at the onset of microalbuminuria was compared with that of 12-wk-old lean Zuc ker rats. Specific (S-35)sulfate incorporation into glomerular PG over 8 h was increased by 57% in obese rats compared with lean rats, sugge sting increased PG synthesis. However, at variance with the observatio n in experimental models of insulin-dependent diabetes mellitus, the p roportion of total glomerular (S-35)PG released by heparin treatment w as unchanged. Heparan sulfate (HS)-PG constituted over 60% of radiolab eled de novo synthesized glomerular PG. Similar proportions of HS-PG w ere extracted from the glomeruli of obese and lean rats. Isolated glom eruli spontaneously released two HS-PG, which constituted approximatel y 30% of total glomerular (S-35)PG. On the basis of their chromatograp hic and electrophoretic patterns, these PG were similar in obese and l ean rats. Heparin treatment of isolated glomeruli released an addition al HS-PG, which appeared to be derived primarily from the glomerulor e xtracellular matrix compartment and not from the detergent soluble cel l fraction. Heparin-releasable HS-PG from both the lean and obese Zuck er rats eluted at a KAV of 0.31 from Sepharose CL-6B chromatographic c olumns, indicating a hydrodynamic size similar to that reported for gl omerular basement membrane HS-PG. However, gel electrophoresis demonst rated faster migration of the HS-PG released by heparin from the glome ruli of obese Zucker rats, suggesting increased electronegativity. Thu s, early in the course of nephropathy in the obese Zucker rat, there i s increased glomerular PG synthesis with no change in the proportions of the constitutively releasable and heparin-releasable HS-PG. Whether electrophoretic abnormalities of the heparin-releasable HS-PG observe d in the obese rats contribute to the development of albuminuria and/o r mesangial matrix expansion remains to be established.