The Reduction Of Renal Injury In Diabetic Dahl Salt-Sensitive Rats With Insulin Is Associated With Decreased Mmp Activity

The current study examined whether treatment with a therapeutic dose of insulin would reduce the progression of renal injury in Dahl salt‐sensitive (SS) rats treated with streptozotocin (STZ). Nine week‐old SS rats were treated with (1) vehicle, (2) STZ (50 mg/kg, i.p.) to induce diabetes and given an insulin implant (2 U/day, s.c) to maintain plasma glucose between 300–400 mg/dL, or (3) STZ and two insulin implants (4 U/day, s.c.) to normalize plasma glucose levels. Rats were fed a low sodium diet containing 0.3% NaCl to minimize the development of hypertension. At 18 weeks of age, proteinuria increased to 302±36 mg/day in STZ SS rats versus 103±13 mg/day in vehicle SS rats. Treatment with a therapeutic dose insulin prevented with severe development of proteinuria in STZ SS rats (101±14 mg/day). The kidneys of STZ SS rats exhibited glomeruloslcerosis and renal fibrosis and the development of renal injury was associated with elevations in matrix metalloproteinase‐2 and ‐9 (MMP‐2 and ‐9) activities in the renal cortex when compared to vehicle‐SS rats. However, administrations of the therapeutic dose of insulin markedly improved the renal histopathology and normalized renal cortical MMP‐2 and ‐9 activities. These results suggest that controlling plasma glucose levels slow the progression of renal disease in this model. The study was supported by a PHRMA Starter grant and NIH grants HL36279 and HL29587.