Gunduz Zubeyde, Dursun Nurcan, Akgun Hulya, Ozturk Figen, Okur Hamit, Koc Nedret
Erciyes University, Medical Faculty, Department of Pediatrics, 38039, Kayseri, Turkey.
Regul Pept. 2005 Dec 15;132(1-3):59-66. doi: 10.1016/j.regpep.2005.09.017. Epub 2005 Oct 17.
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.
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.
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.
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.
瘦素对肾脏病理生理特征具有直接和间接影响。在本研究中，评估了长期输注瘦素对肾脏血流动力学、肾脏排泄功能、转化生长因子-β（TGF-β）表达、血浆内皮素-1（ET-1）水平的影响，以及血管紧张素II 1型受体拮抗剂氯沙坦对这些肾脏变化的预防作用。
本研究使用40只Wistar白化大鼠。在第0天，在无菌条件下经腹腔放置充满瘦素或安慰剂的渗透微型泵。L组（瘦素组，n = 15）和LL组（瘦素-氯沙坦组，n = 15）的大鼠以每小时250 ng的速率给予重组鼠瘦素，持续28天。对照组大鼠（C组，n = 10）以相同的输注速率给予安慰剂。LL组的大鼠还口服氯沙坦（10 mg kg⁻¹ d⁻¹），持续28天。在第28天，将大鼠置于代谢笼中，测定食物和水摄入量，并收集24小时尿液。在研究结束时，直接从左股动脉测定收缩压（SBP）、舒张压（DBP），并使用激光多普勒血流模块间接记录肾血流量（RBF）。
输注瘦素未引起全身动脉血压和尿流率的任何变化。输注瘦素的动物的肌酐（Cr）、钠（Na）和蛋白质排泄率显著增加。氯沙坦治疗使尿Cr和Na排泄减少，而尿蛋白排泄恢复正常。输注瘦素的大鼠循环ET-1水平也较高。氯沙坦治疗使ET-1水平也恢复到正常水平。通过免疫组织化学测定肾脏TGF-β1表达，其在接受瘦素治疗的大鼠的肾小管中更为突出。氯沙坦治疗对肾脏TGF-β1表达无影响。
我们的结果表明，血浆瘦素浓度的病理生理升高导致肾脏Na、Cr和蛋白质排泄增加，以及循环ET-1水平升高。氯沙坦治疗使Na和Cr排泄减少，而蛋白尿和血浆ET-1水平恢复正常，提示肾素-血管紧张素系统激活可能在瘦素诱导的肾脏变化中起作用。TGF-β1可能在瘦素诱导的肾病中起重要作用。
