HIGH GLUCOSE LEVEL UNMASKS A GENETIC PREDISPOSITION TO ENHANCED EXTRACELLULAR-MATRIX PRODUCTION IN MESANGIAL CELLS FROM THE MILAN NORMOTENSIVE STRAIN

A growing body of evidence indicates that the individual genetic backg round plays a role in the pathogenesis of diabetic glomerular disease by either favoring or protecting against injury produced by hyperglyce mia. Two genetically related rat strains, the Milan normotensive strai n (MNS) and the Milan hypertensive strain (MHS) display different susc eptibilities to develop glomerulosclerosis with age. Glomerular sclero sing lesions occur in the MNS rats, which remain normotensive througho ut their entire life-span, but not in the MHS rats, despite the presen ce of arterial hypertension. Previous studies have reported that extra cellular matrix production and cell proliferation increased with donor -aging in mesangial cells isolated from MNS rats, but not in those fro m Mi-IS rats, thus suggesting the existence of an inherited defect in the regulation of cell and matrix turnover, which translates into an a bnormal response to growth-promoting stimuli favoring the development of glomerulosclerosis. In the study presented here, it was hypothesize d that, in addition to donor-aging, other independent risk factors for the development of glomerular disease, such as metabolic injury by hy perglycemia, would be able to trigger and/or precipitate the occurrenc e of these changes in mesangial cells from the susceptible normotensiv e strain, but not in those from the protected hypertensive strain. To test this hypothesis, mesangial cells obtained from these rat strains (before the onset of either glomerulosclerosis or hypertension) were u sed to assess the effects of prolonged (4 wk) exposure to high (30 mmo l/L) versus normal (5.5 mmol/L) glucose concentrations on extracellula r matrix and cytokine production and cell proliferation. The accumulat ion and/or gene expression of the matrix components fibronectin, lamin in, and collagen IV, and of the cytokines insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF-beta) did not change under normal glucose and increased progressively in response to high glucose in both MNS and MI-IS cells. These increases, with the excepti on of the increment in TGF-beta gene expression, were significantly mo re pronounced in MNS cells than in MI-IS cells. In contrast, the proli ferative response to serum was not affected by high glucose, but incre ased in MNS cells, and decreased, although not significantly, in MHS c ells during the 4-wk period, thus mimicking the changes previously obs erved in these rat strains as a function of age. These results indicat e that high glucose unmasks a genetic tendency to produce increasing a mounts of extracellular matrix, not yet evident under normal glucose c onditions, and suggest that a genetically determined propensity of mes angial cells to hyperrespond to chronic hyperglycemia may be implicate d in the pathogenesis of diabetic glomerular disease.