Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat.
Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor-beta (TGF-beta) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-beta and angiotensin II on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (1D11) or human (CAT-192) anti-TGF-beta monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. 1D11 and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and saline, while CAT-192 was ineffective. The addition of either TGF-beta antibody to lisinopril normalized proteinuria. Consistent results were obtained for glomerulosclerosis and tubular damage, which were abrogated by the combined therapy. Interstitial volume expansion and infiltration of lymphocytes/macrophages were limited by 1D11 and lisinopril and further reduced by their combination. The increase of type III collagen in the renal interstitium was partially attenuated by 1D11 and lisinopril while normalized by their combination. It is concluded that anti-TGF-beta antibody when added to a background of chronic angiotensin-converting enzyme (ACE) inhibition fully arrests proteinuria and renal injury of overt diabetic nephropathy, providing a novel route to therapy and remission of disease for diabetic patients who do not respond to RAS inhibition.
Benigni
Ariela
A
Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy.
Zoja
Carla
C
Corna
Daniela
D
Zatelli
Cristina
C
Conti
Sara
S
Campana
Marco
M
Gagliardini
Elena
E
Rottoli
Daniela
D
Zanchi
Cristina
C
Abbate
Mauro
M
Ledbetter
Steve
S
Remuzzi
Giuseppe
G
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D001835:Body Weight; D018932:Chemokine CCL2 / Q000096:biosynthesis; D024061:Collagen Type III / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D003720:Densitometry; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D017706:Lisinopril / Q000627:therapeutic use; D008297:Male; D051379:Mice; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
D000806:Angiotensin-Converting Enzyme Inhibitors; D018932:Chemokine CCL2; D024061:Collagen Type III; D018076:DNA, Complementary; D020033:Protein Isoforms; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017706:Lisinopril