Neutralization of transforming growth factor-beta attenuates hypertension and prevents renal injury in uremic rats.
OBJECTIVE
We investigate the role of transforming growth factor-beta (TGF-beta) in hypertension and renal failure progression in uremic rats, and whether it modulates the endothelin (ET) system.


METHODS
Following renal mass reduction, uremic rats (Nx) received the pan-specific TGF-beta neutralizing antibody 1D11 (0.5 mg/kg, three times/week), the isotype control antibody 13C4 or the AT1 antagonist losartan (10 mg/kg per day) for 6 weeks.


RESULTS
Before treatment, the blood pressure was higher in Nx rats and increased further over time in Nx+13C4 rats. At the end of the study, Nx+13C4 rats exhibited increased serum creatinine, proteinuria and renal expression and excretion of TGF-beta1 and ET-1. ET-1 concentrations were greater in vascular and renal tissues, whereas the ETB receptor expression was reduced. Renal injuries were comprised of blood vessel hypertrophy, glomerular sclerosis, tubular atrophy and interstitial fibrosis, which was associated with increased alpha-smooth muscle actin expression. Treatment of uremic rats with the 1D11 antibody attenuated the increase in blood pressure and the decline in renal function. Losartan normalized the blood pressure and significantly attenuated the increase in serum creatinine and proteinuria. However, both treatments prevented renal TGF-beta1 and ET-1 overexpression, and prevented all renal histological injuries. The 1D11 antibody only improved ETB receptor expression.


CONCLUSIONS
Neutralization of TGF-beta attenuates hypertension and renal failure progression in uremic animals, in part, by preventing renal injury processes. These effects may be related to the modulation of the ET system, preventing renal ET-1 overproduction and the reduction of ETB receptor expression. Our data also suggest that TGF-beta1 is involved, at least in part, in the pathological effects related to angiotensin II in chronic renal failure.
Lavoie
Philippe
P
Research Centre and Division of Nephrology & Hypertension, CHUQ, L'Hôtel-Dieu de Québec Hospital and Department of Medicine, Université Laval, Québec, Canada.
Robitaille
Geneviève
G
Agharazii
Mohsen
M
Ledbetter
Steve
S
Lebel
Marcel
M
Larivière
Richard
R
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D009500:Neutralization Tests; D011507:Proteinuria / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000097:blood / Q000235:genetics / Q000276:immunology*; D014511:Uremia / Q000150:complications*
D047228:Angiotensin II Type 1 Receptor Blockers; D000906:Antibodies; D019332:Endothelin-1; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D016212:Transforming Growth Factor beta; D003404:Creatinine; D019808:Losartan