Fn. Ziyadeh et al., Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice, P NAS US, 97(14), 2000, pp. 8015-8020
Citations number
55
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Emerging evidence suggests that transforming growth factor-beta (TGF-beta)
is an important mediator of diabetic nephropathy. We showed previously that
short-term treatment with a neutralizing monoclonal anti-TGF-beta antibody
(alpha T) in streptozotocin-diabetic mice prevents early changes of renal
hypertrophy and increased matrix mRNA. To establish that overactivity of th
e renal TGF-beta system mediates the functional and structural changes of t
he more advanced stages of nephropathy, we tested whether chronic administr
ation of alpha T prevents renal insufficiency and glomerulosclerosis in the
db/db mouse, a model of type 2 diabetes that develops overt nephropathy. D
iabetic db/db mice and nondiabetic db/m littermates were treated intraperit
oneally with alpha T or control IgG, 300 mu g three times per week for 8 wk
, Treatment with alpha T, but not with IgG, significantly decreased the pla
sma TGF-beta 1 concentration without decreasing the plasma glucose concentr
ation. The IgG-treated db/db mice developed albuminuria, renal insufficienc
y, and glomerular mesangial matrix expansion associated with increased rena
l mRNAs encoding alpha 1(IV) collagen and fibronectin, On the other hand, t
reatment with alpha T completely prevented the increase in plasma creatinin
e concentration, the decrease in urinary creatinine clearance, and the expa
nsion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs
was substantially attenuated, but the excretion of urinary albumin factore
d for creatinine clearance was not significantly affected by alpha T treatm
ent. We conclude that chronic inhibition of the biologic actions of TGF-bet
a with a neutralizing monoclonal antibody in db/db mice prevents the glomer
ulosclerosis and renal insufficiency resulting from type 2 diabetes.