Beneficial Effect of TGFβ Antagonism in Treating Diabetic Nephropathy Depends on When Treatment Is StartedBenigni A. · Zoja C. · Campana M. · Corna D. · Sangalli F. · Rottoli D. · Gagliardini E. · Conti S. · Ledbetter S. · Remuzzi G.
aMario Negri Institute for Pharmacological Research, Bergamo, Italy; bGenzyme Corporation, Framingham, Mass., USA, and cUnit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy
Background: In diabetic rats with maximal activation of RAS induced by uninephrectomy, late treatment with anti-TGFβ antibody limited renal injury only when combined with ACE inhibitor. We investigated whether in a two-kidney diabetic model the time at which treatment started predicted the response to TGFβ antagonist. Methods: 27 weeks after streptozotocin injection, animals had mild proteinuria and were randomized to receive irrelevant antibody, anti-TGFβ antibody (1D11) or enalapril till 52 weeks (early treatment). The effect of agents alone or combined was also evaluated at the time of overt proteinuria (late treatment, 52–61 weeks). Results: When given early, 1D11 displayed marked antihypertensive and antiproteinuric effects. Glomerulosclerosis was reduced to the extent that a remarkable percentage of glomeruli without sclerosis appeared after treatment. Podocyte number was normalized. Renoprotection of 1D11 was comparable to enalapril. Despite control of blood pressure, in late treatment single agents did not reduce proteinuria significantly. Glomerulosclerosis and podocyte loss were partially limited by 1D11 or enalapril, but full protection was achieved by combination. Conclusions: Renoprotective effect of TGFβ antagonism crucially depends on the time at which treatment started. Effectiveness of early treatment with 1D11 would indicate that TGFβ is a major mediator of damage in early diabetes. To tackle the renal damage in the phase of advanced disease, a combined treatment with ACE inhibitor is needed.
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