PubMed · 14630454
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M G Gama, G Rocha. 2003-11-15. The CHARM programme.. https://doi.org/10.1016/s0140-6736(03)14809-x
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BACKGROUND: Leptin has direct and indirect effects on renal pathophysiological characteristics. In the present study, the effects of long-term leptin infusion on the renal hemodynamics, renal excretory functions, and the expression of transforming growth factor-beta (TGF-beta), plasma endothelin-1 (ET-1) levels, and preventive effects of the angiotensin II type 1 receptor antagonist, losartan, on these renal changes were evaluated. METHODS: The study was performed by using forty Wistar albino rats. On day 0, osmotic mini-pumps filled with leptin or placebo were intraperitoneally placed under sterile conditions. The rats in Group L (Leptin group, n=15) and Group LL (Leptin-losartan group, n=15) were given recombinant murine leptin at a rate of 250 ng per hour for 28 days. Control rats (Group C, n=10) were administered placebo at the same infusion rate. The rats in Group LL were also administered losartan (10 mg kg(-1) d(-1)) perorally for 28 days. On day 28, the rats were placed in metabolic cages, and the food and water intakes were determined, and the urine was collected for 24 h. At the end of the study, systolic blood pressure (SBP), diastolic blood pressure (DBP) were determined directly from the left femoral artery, and renal blood flow (RBF) was recorded indirectly using a laser Doppler flow module. RESULTS: Leptin infusion did not produce any changes in systemic arterial blood pressures and urinary flow rate. The rates of creatinine (Cr), sodium (Na), and protein excretions of the animals infused leptin were significantly increased. The urinary Cr and Na excretions were decreased, while the urinary protein excretion was normalized with the losartan treatment. The rats infused leptin had also higher circulating ET-1 levels. ET-1 levels were also reversed to the normal values with the losartan treatment. Renal TGF-beta1 expression was determined immunohistochemically, and it was more prominent in the renal tubules from the rats treated with leptin. The losartan treatment had no effect on renal TGF-beta1 expression. CONCLUSIONS: Our results indicate that pathophysiological increases in plasma leptin concentrations cause enhanced renal Na, Cr and protein excretions, and high circulating ET-1 levels. Na and Cr excretions were decreased, while proteinuria and plasma ET-1 levels were normalized by losartan treatment, suggesting that renin-angiotensin system activation may have a role in leptin induced renal changes. TGF-beta1 may have an important role in leptin induced nephropathy.
We aimed to clarify responsiveness to angiotensin (Ang) II in the porcine basilar artery and the role of Ang II receptor subtypes by functional, radioligand binding, and cell culture studies. Ang II induced more potent contractions in the proximal part than in the distal part of isolated porcine basilar arteries. The contraction induced by Ang II was inhibited by the Ang II type 1 (AT1) receptor antagonist losartan, but the Ang II type 2 (AT2) receptor antagonist PD123319 enhanced it. After removal of the endothelium, the effect of losartan remained but the effect of PD123319 was abolished. The specific binding site of [3H]Ang II on the smooth muscle membrane was inhibited by losartan, but not by PD123319. Stimulation of angiotensin II increased nitric oxide (NO) production in cultured basilar arterial endothelial cells. This production was inhibited by PD123319 and the NO synthase inhibitor L-NG-nitroarginine. These results suggest that the contraction induced by Ang II might be mediated via the activation of AT1 receptors on the basilar arterial smooth muscle cells and be modulated via the activation of AT2 receptors on the endothelial cells, followed by NO production.
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