title: Beneficial effect of TGFbeta antagonism in treating diabetic nephropathy depends on when treatment is started.
abstract: 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.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Bergamo, Italy. abenigni@marionegri.it
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
authors.forename: Carla
authors.initials: C
authors.lastname: Zoja
authors.forename: Marco
authors.initials: M
authors.lastname: Campana
authors.forename: Daniela
authors.initials: D
authors.lastname: Corna
authors.forename: Fabio
authors.initials: F
authors.lastname: Sangalli
authors.forename: Daniela
authors.initials: D
authors.lastname: Rottoli
authors.forename: Elena
authors.initials: E
authors.lastname: Gagliardini
authors.forename: Sara
authors.initials: S
authors.lastname: Conti
authors.forename: Steve
authors.initials: S
authors.lastname: Ledbetter
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000419:Albuminuria / Q000652:urine; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control*; D004656:Enalapril / Q000627:therapeutic use; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D050199:Podocytes / Q000187:drug effects; D011507:Proteinuria / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000906:Antibodies; D016212:Transforming Growth Factor beta; D004656:Enalapril