Although
angiotensin (Ang) II blockade has become a standard antifibrotic
therapy in
kidney disease, the therapeutic efficacy of Ang II blockade is yet to be optimized. Considering the prognostic impact of
proteinuria reduction, we hypothesized that titration of Ang II blockade for optimal anti-proteinuric effect would improve renoprotection. One day after induction of Thy 1.1 glomeruonephritis, rats were treated with increasing doses of the Ang II receptor blocker
valsartan in
drinking water. Six days after disease induction, the
therapeutic effect on
proteinuria, podocyte injury and glomerular
fibrosis was evaluated. Increasing doses of
valsartan resulted in increasing reduction of
proteinuria. The maximally effective dose of
valsartan was determined to be 1000 mg/l, which reduced
proteinuria by 80% and maximally reduced glomerular matrix expansion,
fibronectin,
collagen I and
collagen III staining and glomerular mRNAs for TGFß1,
PAI-1, FN and
collagen I. Notably,
valsartan given at this dose prevented podocyte dysfunction by preserving expression of
podocin and
nephrin and the counter-regulating molecule B7-1 that is involved in podocyte injury. These results support the hypothesis that higher doses of
valsartan are required to optimize
proteinuria reduction and glomerulosclerosis amelioration. Further, the optimal dose of
valsartan also provides an additional
therapeutic effect by preventing podocyte dysfunction.