EFFECT OF GLUCOSE AND HEPARIN ON MESANGIAL ALPHA-1(IV)COLL AND MMP-2 TIMP-2 MESSENGER-RNA EXPRESSION/

Mesangial cells are responsible for the synthesis of mesangial matrix as well as its degradation, which is mediated by a number of proteolyt ic activities, including metalloproteinases (MMPs). Imbalanced matrix protein metabolism may be responsible for mesangial expansion and glom erulosclerosis in diabetic nephropathy. Heparin prevents this complica tion. In human and murine mesangial cell cultures, RT-PCR was able to detect mRNA expression for a number of molecules involved in the mesan gial extracellular matrix turnover: type IV collagen [alpha 1(IV)COLL] , MMP-1, MMP-2, MMP-3, MMP-9 and MMP-10, and the tissue inhibitors TIM P-1 and TIMP-2. The expression of mRNA for alpha 1 (IV)COLL and MMP-2/ TIMP-2 balance was studied in human cells in the presence of high gluc ose and heparin. mRNAs for all the studied molecules were expressed at different levels. Interestingly, a shift in the balance of alpha 1(IV )COLL, MMP-2 and TIMP-2 was observed in high glucose, which was partia lly reversed by heparin supplementation. The new equilibrium was mostl y due to the down-regulation of type IV collagen expression, rather th an further reduction of potential proteolysis. Our data, while extendi ng the list of potential mediators of mesangial matrix catabolism, hig hlight a molecular mechanism by which the pathogenesis of diabetic nep hropathy may be sustained, and at the same time suggest that heparin m ay have the potential to correct this abnormality.