Urinary Transforming Growth Factor-β Excretion in Patients With Hypertension, Type 2 Diabetes, and Elevated Albumin Excretion Rate

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Abstract
OBJECTIVE—Transforming growth factor-β (TGF-β) is a prosclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. In addition to high glucose, other factors implicated in renal fibrosis and increased TGF-β synthesis include angiotensin II and high dietary sodium intake. The aim of this study was to examine the effect of angiotensin receptor blockade (ARB) and dietary sodium restriction on the plasma concentration and urinary excretion of TGF-β in hypertensive patients with type 2 diabetes and elevated albumin excretion rate (AER). RESEARCH DESIGN AND METHODS—Twenty-one subjects with hypertension and AER between 10 and 200 μg/min were randomized to receive either 50 mg losartan daily (n = 11) or placebo (n = 10). Drug therapy was given in two 4-week phases, separated by a 4-week washout period. In the last 2 weeks of each phase, patients were assigned to regular- or low-sodium diets in random order. Parameters measured at week 0 and 4 of each phase included plasma TGF-β concentration, TGF-β urinary excretion, AER, clinic mean arterial blood pressure, and urinary sodium excretion. RESULTS—Plasma TGF-β was unaffected by losartan treatment or sodium intake. In the losartan group, urinary TGF-β excretion decreased by 23.2% (−39.2 and 13.6) [median (interquartile range)] and 38.5% (−46.8 and −6.1) in the regular- and low-sodium phases, respectively (P < 0.05 for drug effect). In the placebo group, median changes of 0.0% (−12.1 and 44.4) and 0.0% (−29.2 and 110.7) occurred in the regular- and low-sodium phases, respectively. Sodium restriction did not affect urinary TGF-β excretion in either losartan- or placebo-treated patients (P = 0.54 for overall dietary effect), and there was no evidence of interaction between drug and diet (P = 0.29). CONCLUSIONS—In hypertensive type 2 diabetic patients with elevated AER, the ARB losartan, but not sodium restriction, reduced urinary TGF-β excretion. These data suggest that the renoprotective effects of losartan in patients with type 2 diabetes and nephropathy may include a reduction in renal TGF-β production.