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Effects of Losartan on Expression of NHE3 in Renal Tubule and Renal Protection of Spontaneously Hypertensive Rats

Author: FanXiaoQin
Tutor: GaoYuan
School: Zunyi Medical College,
Course: Physiology
Keywords: Losartan Spontaneously hypertensive rats SGK1 protein NHE3 protein Oxidative Stress Renal function
CLC: R544.1
Type: Master's thesis
Year: 2010
Downloads: 53
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Abstract

Objective: To observe the first part of losartan on the spontaneously hypertensive rat renal tubular sodium / hydrogen exchange protein 3 isoforms losartan in spontaneously hypertensive rats (in spontaneously hypertensive rat, SHR) renal tubular sodium / hydrogen exchange protein 3 subtypes (Sodium hydrogen exchanger isform 3 of NHE3) expression of the impact, and explore the serum and glucocorticoid-induced protein kinase 1 (Serum and glucocorticoid inducible kinase 1, SGK1) expression changes observed losartan in affect the SHR renal tubular NHE3 expression with the SGK1 expression changes provide a new basis for an in-depth understanding of the pharmacodynamic mechanism of losartan antihypertensive new role for the research and development of new anti-hypertensive drugs targets. Methods: 12 spontaneously hypertensive rats were randomly divided into losartan the intragastric group (Los group) and solvent gavage group (SHR group) 6 groups; Wistar Kyoto rats (WKY group) 6 blank control group. The the Los group per 30mg/kg/day orally rats the WKY group and solvent SHR group fed daily volume of solvent. Weekly adjustment of drug dose based on body weight of rats once; intragastric administration of up to 18 weeks of age. Every two weeks, systolic blood pressure measured tail cuff method. Collected plasma and kidney, rat plasma and kidney tissue angiotensin Ⅱ (Angiotensin Ⅱ, Angll) level was measured by radioimmunoassay; real-time quantitative PCR detection of rat renal tubular SGK1 of NHE3 mRNA expression changes; immunohistochemistry peroxidase method and image analysis is the determination of the localization and expression of renal NHE3 protein. Results: SHR group systolic blood pressure higher than WKY group (P lt; 0.01), the Los group from 10w chlorine Chastain ig 2w, systolic blood pressure was significantly lower than that in the SHR group (P lt; 0.05) in the subsequent 6w time continuous losartan gavage, systolic blood pressure steady decline (P lt; 0.01); after intragastric administration 8w, Los plasma Ang Ⅱ levels significantly higher than WKY group (P lt; 0.05), with SHR group without significantly with sex differences (P gt; 0.05); Los group kidney tissue of Ang Ⅱ level is also significant with higher than WKY group (P lt; 0.05), compared with the SHR group, also no significant sex difference (P gt; 0.05); 3, real-time quantitative PCR results show that relative to the normal WKY group, the SHR group tubular NHE3mRNA expression levels increased 2.3-fold, Los group increased by only 1.65 times; immunohistochemical staining results show that: relative to WKY group solvent the SHR group of NHE3 protein in renal tubular epithelial cells was significantly strong positive expression of the highest, the lowest score of the gray values; were moderately strong positive the Los group NHE3 protein in renal tubular epithelial cells, increase the amount of protein. Compared with WKY, the SHR group tubular SGK1mRNA expression levels increased by 3.31 times, while the Los group increased by only 1.84 times. Conclusion: the spontaneously hypertensive rat plasma and renal tissue RAS generally activated losartan does not inhibit the activation of RAS. 2, spontaneously hypertensive rats the tubular NHE3mRNA and protein are abnormal overexpression of the AT1 receptor activation is one of the reasons this overexpression. Spontaneously hypertensive rat kidney SGK1mRNA AT1 receptor-mediated abnormal overexpression, which may NHE3 overexpression of intermediate links. Hypertension, losartan pharmacodynamic mechanism may involve non-peptide antagonist of the AT1 receptor on tubular SGKl and NHE3 overexpression restrictions. 5, losartan has time consistency on spontaneously hypertensive rat renal tubular SGK1 and NHE3 overexpression restrict their antihypertensive efficacy. Objective: To observe the second part of the Losartan oxidative stress in spontaneously hypertensive rats and renal function the Losartan spontaneously hypertensive rats oxidative stress and renal function, investigate losartan on hypertension protection mechanisms of kidney damage. Methods: 12 spontaneously hypertensive rats were randomly divided into losartan the intragastric group (Los group) and solvent gavage group (SHR group) 6 groups; Wistar Kyoto rats (WKY group) 6 blank control group. The the Los group per 30mg/kg/day orally rats the WKY group and solvent SHR group fed daily volume of solvent. Weekly adjustment of drug dose based on body weight of rats once; intragastric administration of up to 18 weeks of age. Collect urine, serum and kidney. HE staining of the renal tissue morphological changes; radioimmunoassay (radioimmunoassay, RIA) determination of the content of the urine β2-microglobulin (β2-micro globulin, β2-MG); colorimetric determination of serum creatinine in serum (Serum creatinine , SCr), blood urea nitrogen (Blood urea nitrogen, BUN), serum and renal tissue nitric oxide (Nitric oxide, NO), superoxide dismutase (Superoxide dismutase, SOD), malondialdehyde (Maleic dialdehyde, MDA ) levels. Results: Compared with 18-week-old WKY group solvent gavage SHR rats serum and renal tissue NO, SOD were significantly lower (P lt; 0.01; P lt; 0.01), but the MDA levels were significantly higher (P lt; 0.01); Los group after losartan continuous drenching 8w, serum and renal tissue NO, SOD levels compared with the SHR group was significantly higher (P lt; 0.05; P lt; 0.05), MDA content lower (P lt; 0.05); 2. comparison with the 18-week-old WKY group solvent gavage the SHR rat serum SCr level increased slightly but no significant differences (P gt; 0.05); serum BUN and urinary β2- microglobulin increased significantly (P lt; 0.05; P lt; 0.01), the Los group 8w after intragastric administration of losartan, serum BUN and urinary β2-microglobulin significantly lower (P lt; 0.05; P lt; 0.01 ). Conclusion: 1. Oxidative stress may be involved in the pathogenesis of hypertensive renal damage; losartan have a protective effect in spontaneously hypertensive renal damage; 3. Protection of losartan in spontaneously hypertensive nephropathy may part by improving the role of oxidative stress.

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