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 Table of Contents  
BRIEF COMMUNICATION
Year : 2019  |  Volume : 10  |  Issue : 1  |  Page : 64

Protective role of angiotensin Type 1 receptor blockade in 4/6 nephrectomized male and female rats


1 Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
2 Water and Electrolytes Research Center; Department of Physiology, Isfahan University of Medical Sciences; Isfahan MN Institute of Basic and Applied Sciences Research, Isfahan, Iran

Date of Submission06-Jul-2017
Date of Acceptance22-Oct-2017
Date of Web Publication17-May-2019

Correspondence Address:
Mehdi Nematbakhsh
Department of Physiology, Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpvm.IJPVM_278_17

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  Abstract 


Background: Chronic kidney disease associated with serious morbidity and mortality rate while it is affected by renin-angiotensin system. The effects of losartan as angiotensin II Type 1 receptor antagonist on renal functional in 4/6 nephrectomized rats was evaluated. Methods: Twenty-six male and female Wistar rats underwent 4/6 nephrectomy, and the animals from each gender were randomly divided into two groups which treated with vehicle and losartan (10 mg/kg/day for 1 week). The parameters related to kidney function were measured. Results: Creatinine (Cr) clearance and urine flow were improved in losartan-treated group significantly (P < 0.05). The serum level of blood urea nitrogen and Cr and kidney tissue damage score and sodium urinary output (UNaV) did not alter. However, losartan decreased percentage of sodium excretion (ENa%) in both genders insignificantly. Conclusions: Losartan may improve renal function in 4/6 nephrectomized male rats.

Keywords: Losartan, nephrectomy, rat


How to cite this article:
Moeini M, Talebi A, Nematbakhsh M. Protective role of angiotensin Type 1 receptor blockade in 4/6 nephrectomized male and female rats. Int J Prev Med 2019;10:64

How to cite this URL:
Moeini M, Talebi A, Nematbakhsh M. Protective role of angiotensin Type 1 receptor blockade in 4/6 nephrectomized male and female rats. Int J Prev Med [serial online] 2019 [cited 2019 Jun 19];10:64. Available from: http://www.ijpvmjournal.net/text.asp?2019/10/1/64/258461




  Introduction Top


The renin-angiotensin system (RAS) has an important role in the progression of renal disease and kidney pathomorphologic alteration. These changes include tubulointerstitial fibrosis, tubular atrophy, inflammation, and glomerulosclerosis.[1] The major biologic actions of angiotensin II (Ang II) is mediated by Ang II Types 1 and 2 receptors (AT1R and AT2R).[2] Pro-inflammatory effects, stimulation of tubular transport, vasoconstriction, aldosterone release, and growth stimulatory actions, are mediated by AT1R,[2],[3] whereas AT2R activation is vasodilation through the formation of bradykinin and nitric oxide.[4] In addition, the studies have demonstrated that RAS functions act gender dependently.[5] RAS and its receptor blockades plays an important role in decreasing chronic renal failure (CRF) progression and improve kidney tissue damage.[6],[7] The role of losartan is reported in acute and CRF;[8],[9] however, its gender-related effects is not completely known. Therefore, this study was designed to determine the effect of AT1R antagonist (losartan) on 4/6 nephrectomized male and female rats.


  Methods Top


Animals

A total of 26 male and female Wistar rats (Animal Center, Isfahan University of Medical Sciences, Isfahan, Iran) were used in this research study. The rats were housed at a temperature of 23°C–25°C with a 12 h light/dark cycle and they had free access to water rat chow. All experiments were approved by the Isfahan University of Medical Sciences Ethics Committee.

Experimental protocol

Rats were anesthetized with chloral hydrate (450 mg/kg, ip) and underwent 4/6 nephrectomy (4/6 NX) by the removal of the right kidney and ablation approximately of one-thirds of the left kidney (lower pole). The rats from each gender were randomly divided into two groups: 4/6 nephrectomized group (named vehicle group) and 4/6 nephrectomized losartan-treated group (named losartan group).

Losartan (10 mg/kg/day. ip) and vehicle were administrated 2 h before surgery and continued daily for 1 week. At the last day of experiment, the rats were placed in metabolic cages for 6 h to collect urine volume and urine flow (UF). Finally, blood samples were obtained, and the animals were sacrificed humanly.

The testis, uterus, and remnant kidney tissues were removed and weighted, and the kidney tissue was fixed in 10% formalin embedded in paraffin for histopathological staining. The hematoxylin and eosin stain was applied to examine the tissue injury. Kidney tissue damage score (KTDS) was evaluated by the presence of tubular atrophy, hyaline cast, debris, and vacuolization as 1–4 while zero score was assigned to normal tissue.

Measurements

The serum and urine sodium concentrations were determined by flame photometer. The serum levels of creatinine (Cr) and blood urea nitrogen (BUN) were measured by autoanalyzer (Technicon, Ireland Ltd.) using Pars Azmoon Kits (Tehran, Iran). The serum nitrite level was measured by Griess method.

Statistical analysis

Data are expressed as mean ± standard error of mean. Statistical analysis was performed using Kruskal–Wallis and Mann–Whitney test pathology data. Comparisons among independent samples were analyzed by Student's t-test. Statistical significance was accepted when P ≤ 0.05.


  Results Top


UF and Cr clearance were increased significantly in losartan-treated groups in male rats (P < 0.05), but such observations were not observed in female animals. Losartan attenuated the body weight change (ΔBW) in female significantly (P < 0.05) [Table 1]. The serum levels of Cr, BUN and nitrite, and tissues (kidney, testis, and uterus) weight per 100 g body weight, KTDS, and sodium urinary output per gram kidney tissue (UNaV) were not significantly different between losartan- and vehicle-treated groups in both genders [Figure 1] and [Table 1]. In addition, the percentage of sodium excretion (ENa%) was decreased in losartan groups insignificantly.
Table 1: Kidney tissue damage score, remnant kidney weight/100 g body weight, uterus weight/100 g body weight, testis weight/100 g body weight, body weight change (g), and serum nitrite (μmole/l) in 4/6 nephrectomized animals

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Figure 1: The serum levels of blood urea nitrogen and creatinine, and creatinine clearance, urine flow, sodium urinary output per gram kidney tissue, and percentage of sodium excretion (ENa%) in losartan- and vehicle-treated 4/6 nephroctomized male and female rats. Star (*) represents significant difference from vehicle group in the same gender (P < 0.05)

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  Discussion Top


Some clinical and experimental animal studies have found evidence for the upregulation of RAS system in the progression of renal disease,[10],[11] and AT1R blockade may improve impaired kidney.[6],[12] The effects of losartan through decreasing of inflammation, blood pressure, platelet activation and aggregation, and increasing of vasodilation and glomerular filtration rate (GFR) have been reported.[13],[14],[15] In the present study, we showed the effects of losartan on renal function in 4/6 nephroctomized male and female rats, and the major findings indicated that losartan increased Cr clearance and UF in both genders; however, it was significant only in male rats. The increased UF in losartan-treated male rats was not related to sodium excretion since ENa% in losartan group was lower than vehicle-treated group [Figure 1]. It seems that the reason is related to GFR increasing by losartan while Cr clearance was also increased. UF and Cr clearance also were increased in female rats treated with losartan insignificantly. Possibly, the animal sample size was not large or the dose of losartan was not enough since an experimental study showed that renal protection by losartan was dose-related.[16] Kidney functional factors such as BUN and Cr did not alter. Our findings corroborate the previous report that has shown neither BUN nor Cr altered after 8-week losartan therapy (20 mg/kg/day) on isolated mesenteric resistance arteries in 5/6 nephrectomized rats.[17] It is concluded that losartan can improve Cr clearance, UF and ENa% without alteration of BUN and Cr in 4/6 nephrectomized in male. More studies in female with different doses of losartan are needed.

Financial support and sponsorship

This research was supported by Isfahan University of Medical Sciences (Grant #294249).

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006;116:288-96.  Back to cited text no. 1
    
2.
Wolf G, Butzmann U, Wenzel UO. The renin-angiotensin system and progression of renal disease: From hemodynamics to cell biology. Nephron Physiol 2003;93:P3-13.  Back to cited text no. 2
    
3.
Brewster UC, Perazella MA. The renin-angiotensin-aldosterone system and the kidney: Effects on kidney disease. Am J Med 2004;116:263-72.  Back to cited text no. 3
    
4.
Carey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000;35:155-63.  Back to cited text no. 4
    
5.
Sandberg K, Ji H. Sex and the renin angiotensin system: Implications for gender differences in the progression of kidney disease. Adv Ren Replace Ther 2003;10:15-23.  Back to cited text no. 5
    
6.
Haghighi M, Nematbakhsh M, Talebi A, Nasri H, Ashrafi F, Roshanaei K, et al. The role of angiotensin II receptor 1 (AT1) blockade in cisplatin-induced nephrotoxicity in rats: gender-related differences. Ren Fail. 2012;34(8):1046-51.  Back to cited text no. 6
    
7.
Azizi M, Ménard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 2004;109:2492-9.  Back to cited text no. 7
    
8.
Cheng SY, Chou YH, Liao FL, Lin CC, Chang FC, Liu CH, et al. Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury. Sci Rep 2016;6:34265.  Back to cited text no. 8
    
9.
Dionisio P, Valenti M, Caramello E, Bergia R, Cravero R, Berto IM, et al. Acute kidney failure and losartan: A recently observed event of antagonists of angiotensin II AT1 receptors. Minerva Urol Nefrol 2000;52:123-5.  Back to cited text no. 9
    
10.
Ots M, Mackenzie HS, Troy JL, Rennke HG, Brenner BM. Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation. J Am Soc Nephrol 1998;9:224-30.  Back to cited text no. 10
    
11.
Bader M. Tissue renin-angiotensin-aldosterone systems: Targets for pharmacological therapy. Annu Rev Pharmacol Toxicol 2010;50:439-65.  Back to cited text no. 11
    
12.
Moslemi F, Taheri P, Azimipoor M, Ramtin S, Hashemianfar M, Momeni-Ashjerdi A, et al. Effect of angiotensin II type 1 receptor blockade on kidney ischemia/reperfusion; a gender-related difference. J Renal Inj Prev. 2016; 28;5:140-3.   Back to cited text no. 12
    
13.
Siragy HM, Jaffa AA, Margolius HS, Carey RM. Renin-angiotensin system modulates renal bradykinin production. Am J Physiol 1996;271:R1090-5.  Back to cited text no. 13
    
14.
Ruiz-Ortega M, Esteban V, Rupérez M, Sánchez-López E, Rodríguez-Vita J, Carvajal G, et al. Renal and vascular hypertension-induced inflammation: Role of angiotensin II. Curr Opin Nephrol Hypertens 2006;15:159-66.  Back to cited text no. 14
    
15.
Li P, Ferrario CM, Brosnihan KB. Losartan inhibits thromboxane A2-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats. J Cardiovasc Pharmacol 1998;32:198-205.  Back to cited text no. 15
    
16.
Fujihara CK, Velho M, Malheiros DM, Zatz R. An extremely high dose of losartan affords superior renoprotection in the remnant model. Kidney Int 2005;67:1913-24.  Back to cited text no. 16
    
17.
Kööbi P, Kalliovalkama J, Jolma P, Rysä J, Ruskoaho H, Vuolteenaho O, et al. AT1 receptor blockade improves vasorelaxation in experimental renal failure. Hypertension 2003;41:1364-71.  Back to cited text no. 17
    


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