Reversibility of established diabetic glomerulopathy by anti-TGF-beta antibodies in db/db mice.
Treatment with a neutralizing anti-transforming growth factor-beta (TGF-beta) antibody can prevent the development of diabetic nephropathy in the db/db mouse, a model of type 2 diabetes. However, it is unknown whether anti-TGF-beta therapy can reverse the histological lesions of diabetic glomerulopathy once they are established. Diabetic db/db mice and their non-diabetic db/m littermates were allowed to grow until 16 weeks of age, by which time the db/db mice had developed glomerular basement membrane (GBM) thickening and mesangial matrix expansion. The mice were then treated with an irrelevant control IgG or a panselective, neutralizing anti-TGF-beta antibody for eight more weeks. Compared with control db/m mice, the db/db mice treated with IgG had developed increased GBM width (16.64+/-0.80 nm vs. 21.55+/-0.78 nm, P<0.05) and increased mesangial matrix fraction (4.01+/-0.81% of total glomerular area vs. 9.55+/-1.04%, P<0.05). However, the db/db mice treated with anti-TGF-beta antibody showed amelioration of GBM thickening (18.40+/-0.72 nm, P<0.05 vs. db/db-IgG) and mesangial matrix accumulation (6.32+/-1.79%, P<0.05 vs. db/db-IgG). Our results demonstrate that inhibiting renal TGF-beta activity can partially reverse the GBM thickening and mesangial matrix expansion in this mouse model of type 2 diabetes. Anti-TGF-beta regimens would be useful in the treatment of diabetic nephropathy.
Chen
Sheldon
S
Renal-Electrolyte and Hypertension Division, Penn Center for the Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania, 700 Clinical Research Building, 415 Curie Boulevard, Philadelphia 19104, USA.
Iglesias-de la Cruz
M Carmen
MC
Jim
Belinda
B
Hong
Soon Won
SW
Isono
Motohide
M
Ziyadeh
Fuad N
FN
D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D001786:Blood Glucose / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D005260:Female; D005920:Glomerular Mesangium / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009500:Neutralization Tests; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology
D001786:Blood Glucose; D007074:Immunoglobulin G; D016212:Transforming Growth Factor beta