Nephropathy develops in many but not all patients with long-standing
type 1 diabetes. Substantial efforts to identify genotypic differences explaining this differential susceptibility have been made, with limited success. Here, we show that the expression of the
transforming growth factor β1 gene (Tgfb1) affects the development of
diabetic nephropathy in mice. To do this we genetically varied Tgfb1 expression in five steps, 10%, 60%, 100%, 150%, and 300% of normal, in mice with
type 1 diabetes caused by the Akita mutation in the
insulin gene (Ins2(Akita)). Although plasma
glucose levels were not affected by Tgfb1 genotype, many features of
diabetic nephropathy (mesangial expansion, elevated plasma
creatinine and
urea, decreased
creatinine clearance and
albuminuria) were progressively ameliorated as Tgfb1 expression decreased and were progressively exacerbated when expression was increased. The diabetic 10% hypomorphs had comparable
creatinine clearance and
albumin excretion to wild-type mice and no harmful changes in renal morphology. The diabetic 300% hypermorphs had ∼1/3 the
creatinine clearance of wild-type mice, >20× their
albumin excretion, ∼3× thicker glomerular basement membranes and severe podocyte effacement, matching human
diabetic nephropathy. Switching Tgfb1 expression from low to high in the tubules of the hypomorphs increased their
albumin excretion more than 10-fold but
creatinine clearance remained high. Switching Tgfb1 expression from low to high in the podocytes markedly decreased
creatinine clearance, but minimally increased
albumin excretion. Decreasing expression of Tgfb1 could be a promising option for preventing loss of renal function in diabetes.