Normalizing glycated albumin reduces increased urinary collagen IV and prevents renal insufficiency in diabetic db/db mice

Increased excretion of type IV collagen accompanies the accumulation of mesangial matrix, which leads to compromise in the glomerular filtration surface area, during the development of diabetic nephropathy. We postulated that the response of urinary collagen IV would be useful in evaluating possible treatment strategies to arrest the nephropathic process while still at a reversible stage. To test this hypothesis, we examined the effect of a small molecule (22CPPA) that inhibits the formation of glycated albumin, which is causally linked to the pathogenesis of diabetic nephropathy, on collagen IV excretion, albuminuria, and renal function in db/db mice. Compared to nondiabetic db/m mice, db/db animals showed markedly increased urinary collagen IV and albumin, significantly elevated serum glycated albumin and creatinine concentrations, and a significantly reduced creatinine clearance. Treatment of db/db mice with test compound, which normalized glycated albumin concentrations, significantly lowered collagen IV and albumin excretion and ameliorated the fall in creatinine clearance and the rise in serum creatinine despite persistent hyperglycemia. The findings indicate that reduction of elevated collagen IV excretion in diabetes reflects a salutary influence on developing glomerulosclerosis, and that glycated albumin has an important nephropathogenic role that can be therapeutically addressed independent of glycemic status.