Effects of losartan on urinary secretion of extracellular matrix and their modulators in type 2 diabetes mellitus patients with microalbuminuria.
OBJECTIVE
Angiotensin II receptor Type 1 antagonists postpone the development of nephropathy in type 2 diabetes mellitus (DM). We hypothesize that Losartan may ameliorate renal function in diabetic patients through the regulation on the generation of transforming growth factor (TGF)-beta and fibrinolytic regulators.


METHODS
Twenty-two type 2 DM patients with microalbuminuria were treated with 50-100 mg/day of Losartan for 6 months. Urinary secretion of TGF-, plasminogen activator inhibitor-1 (PAI-1), tissue and urokinase plasminogen activators (tPA and uPA) fibronectin, collagen IV and plasma levels of TGF-beta, PAI-1, tPA and uPA of the patients before and after the treatment were analyzed using enzyme-linked immunoabosorbance assay.


RESULTS
Losartan effectively reduced arterial blood pressure and urinary albumin excretion. The levels of TGF-beta in urine, but not in plasma, were reduced after 2, 4 and 6 months of the treatment (-32% to -48%, P < 0.05 or 0.01). Urinary or plasma levels of PAI-1, tPA or uPA, and urinary secretion of fibronectin or collagen IV were not significantly altered by Losartan treatment. Urinary levels of collagen IV positively correlated with uPA, and that of fibronectin negatively correlated with PAI-1 in the patients (P < 0.01). Urinary TGF-beta negatively correlated uPA in urine of the patients (P < 0.01).


CONCLUSIONS
Losartan reduced urinary excretion of TGF-beta and albumin in type 2 DM patients with microalbuminuria. Fibrinolytic regulators and TGF-beta are implicated in the regulation of ECM turnover in kidneys of the patients with diabetic nephropathy.
Woo
Vincent
V
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Ni
Lian-Song
LS
Hak
Dixie
D
Berard
Lori
L
Zhu
Fuqin
F
Khan
Shagufta
S
Ma
Guoping M
GM
Penner
Brian
B
Shen
Garry X
GX
D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000150:complications / Q000188:drug therapy* / Q000652:urine; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D001779:Blood Coagulation Factors / Q000032:analysis / Q000652:urine*; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D024141:Collagen Type IV / Q000652:urine; D003401:Creatine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D016326:Extracellular Matrix Proteins / Q000652:urine*; D005260:Female; D005353:Fibronectins / Q000652:urine; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D008055:Lipids / Q000097:blood; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000652:urine; D010960:Plasminogen Activators / Q000097:blood / Q000652:urine; D011188:Potassium / Q000097:blood; D012044:Regression Analysis; D016212:Transforming Growth Factor beta / Q000097:blood / Q000652:urine; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; D001779:Blood Coagulation Factors; D002784:Cholesterol; D024141:Collagen Type IV; D003401:Creatine; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D006442:Glycated Hemoglobin; D008055:Lipids; D019808:Losartan; D017395:Plasminogen Activator Inhibitor 1; D010960:Plasminogen Activators; D011188:Potassium; D016212:Transforming Growth Factor beta