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Beneficial effect of TGFbeta antagonism in treating diabetic nephropathy depends on when treatment is started
Ariela Benigni1, Carla Zoja, Marco Campana
1Mario Negri Institute for Pharmacological Research, Bergamo, Italy. abenigni@marionegri.it
Background:
In diabetic rats with maximal activation of RAS induced by uninephrectomy, late treatment with anti-TGFbeta 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 TGFbeta antagonist.
Methods:
27 weeks after streptozotocin injection, animals had mild proteinuria and were randomized to receive irrelevant antibody, anti-TGFbeta 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 TGFbeta antagonism crucially depends on the time at which treatment started. Effectiveness of early treatment with 1D11 would indicate that TGFbeta 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.
Insights
Early TGF-beta antagonism shows promise for diabetic kidney disease, but advanced stages require combination therapy with ACE inhibitors for full renoprotection.
Area of Science:
- Nephrology
- Diabetology
- Pharmacology
Background:
- Diabetic kidney disease involves activated renin-angiotensin system (RAS).
- Early studies showed anti-TGF-beta antibody combined with ACE inhibitor limited renal injury in diabetic rats.
- The predictive role of treatment timing on TGF-beta antagonist response was investigated.
Purpose of the Study:
- To determine if the timing of treatment initiation affects the renoprotective response to a TGF-beta antagonist in a two-kidney diabetic rat model.
- To compare the efficacy of early versus late treatment with anti-TGF-beta antibody (1D11) and enalapril, alone or in combination.
Main Methods:
- Diabetic rats (27 weeks post-streptozotocin) with mild proteinuria were randomized to early treatment (until 52 weeks) with irrelevant antibody, 1D11, or enalapril.
- Late treatment (52-61 weeks) evaluated agents alone or combined in animals with overt proteinuria.
- Renal injury markers, blood pressure, proteinuria, glomerulosclerosis, and podocyte count were assessed.
Main Results:
- Early 1D11 treatment demonstrated significant antihypertensive and antiproteinuric effects, comparable to enalapril.
- Early 1D11 normalized podocyte number and markedly reduced glomerulosclerosis.
- Late treatment with single agents showed limited efficacy; combination therapy (1D11 + enalapril) was required for full renoprotection in advanced disease.
Conclusions:
- The renoprotective efficacy of TGF-beta antagonism is critically dependent on the initiation timing.
- Early TGF-beta antagonism suggests TGF-beta is a key mediator in early diabetic kidney damage.
- Combined therapy with an ACE inhibitor is necessary to manage renal damage in advanced diabetic kidney disease.
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