The effect of angiotensin 1-7 and losartan on renal ischemic/reperfusion injury in male rats

Tahereh Safari , Mohamad Reza Shahraki, Saideh Miri, Nasime Mirakzehi Bakhshani, Abbass Ali Niazi, Gholam Reza Komeili, Hossain Bagheri


Ischemia/reperfusion (I/R) is a major cause of acute kidney injury. Several studies have shown that renin angiotensin (Ang) system and activation of Ang II type 1 receptor (AT1) are involved in various forms of kidney diseases. Likewise, Ang 1-7 as a physiologic antagonist of AT1 and losartan could possibly protect the kidney against I/R damage. Therefore, we investigated renal injury by administering the drugs before and after I/R. Fifty-four male Wistar rats were randomly assigned to five groups as follows. 1, Sham operated; 2, saline group (as a control group); 3, losartan group; 4, Ang 1-7group; and 5, Ang 1-7 + losartan simultaneously. It should be noted that groups 2-5 consisted of two separate I/R-induced subgroups both receiving medication where the first groups received the treatment 15 min before induction of I/R while the medications were given to the second groups immediately after induction of I/R. Twenty four h after I/R, blood samples were collected, and then levels of serum urea nitrogen (BUN), creatinine (Cr), nitrite, malondialdehyde (MDA), lactate dehydrogenase (LDH) and total antioxidant capacity (TAC) were measured. Likewise, nitrite, MDA and TAC were measured in the homogenized kidney tissues. After the induction of I/R, the BUN, Cr, LDH, and kidney tissue damage score increased. Administration of Ang 1-7 alone or simultaneously with losartan decreased the levels of aforementioned factors. Also,kidney MDA and nitrate levels significantly increased after I/R induction (P < 0.05). According to the results of this study, it can be claimed that the effect of losartan in the presence of Mas receptor is statistically significant and kidney damage dramatically decreases.


Angiotensin 1-7; Ischemia/reperfusion; Losartan; Renal damage.

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Fang F, Liu GC, Zhou X, Yang S, Reich HN, Williams V, et al. Loss of ACE2 exacerbates murine renal ischemia-reperfusion injury. PloS One. 2013;8(8):e71433.

Bazzano T, Restel TI, Porfirio LC, Souza AS, Silva IS. Renal biomarkers of male and female Wistar rats (Rattus norvegicus) undergoing renal ischemia and reperfusion. Acta Cir Bras. 2015;30(4):277-288.

Lai CF, Wu VC, Huang TM, Yeh YC, Wang KC, Han YY, et al. Kidney function decline after a non-dialysis-requiring acute kidney injury is associated with higher long-term mortality in critically ill survivors. Crit Care. 2012;16(4): R123-R132.

Peeters P, Terryn W, Vanholder R, Lameire N. Delayed graft function in renal transplantation. Curr Opin Crit Care. 2004;10(6):489-498.

Devarajan P. Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol. 2006;17(6):1503-1520.

Bonventre JV, Zuk A. Ischemic acute renal failure: an inflammatory disease? Kidney Int. 2004;66(2): 480-485.

Ruiz-Ortega M, Rupérez M, Esteban V, Rodríguez-Vita J, Sanchez-Lopez E, Carvajal G, et al. Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases. Nephrol Dial Transplant. 2006;21(1):16-20.

Rüster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol. 2006;17(11):2985-2991.

Allred AJ, Chappell MC, Ferrario CM, Diz DI. Differential actions of renal ischemic injury on the intrarenal angiotensin system. Am J Physiol Renal Physiol. 2000;279(4):F636-F645.

Touyz RM, Schiffrin EL. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev. 2000;52(4):639-672.

Chan JC, Ko GT, Leung DH, Cheung RC, Cheung MY, So WY, et al. Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. Kidney Int. 2000;57(2):590-600.

Ferreira AJ, Santos RA, Bradford CN, Mecca AP, Sumners C, Katovich MJ, et al. Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension. 2010;55(2):207-213.

Santos RA, Ferreira AJ, e Silva ACS. Recent advances in the angiotensin‐converting enzyme 2-angiotensin (1-7)-Mas axis. Exp Physiol. 2008;93(5):519-527.

Nematbakhsh M, Safari T. Role of Mas receptor in renal blood flow response to angiotensin (1-7) in male and female rats. Gen Physiol Biophys. 2014;33(3):365-372.

Ren Y, Garvin JL, Carretero OA. Vasodilator action of angiotensin-(1-7) on isolated rabbit afferent arterioles. Hypertension. 2002;39(3):799-802.

Wong DW, Oudit GY, Reich H, Kassiri Z, Zhou J, Liu QC, et al. Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury. Am J Pathol. 2007;171(2):438-451.

Hassanshahi J, Maleki M, Nematbakhsh M. Renin-angiotensin system and unilateral ureteral obstruction. Physiol Pharmacol. 2017; 21(4): 266-278.

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):1046-1051.

Forte BL, Slosky LM, Zhang H, Arnold MR, Staatz WD, Hay M, et al. Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone pain. Pain. 2016;157(12):2709-2721.

Miri S, Safari T, Komeili GR, Nematbakhsh M, Niazi AA, Jahantigh M, et al. Sex difference in gentamicin-induced nephrotoxicity: influence of L-arginine in rat model. Int J Prev Med. 2018;9: 108-123.

Safari T, Miri S, Ghofran O, Fereidooni F, Niazi AA, Baghei H, et al. Gender differences in response to vitamin E and C in gentamicin induced nephrotoxicity in Wistar rats. J Nephropathol. 2017;6(4):338-345.

Heitsch H, Brovkovych S, Malinski T, Wiemer G. Angiotensin-(1-7)-stimulated nitric oxide and superoxide release from endothelial cells. Hypertension. 2001;37(1):72-76.

Ueda S, Masumori-Maemoto S, Wada A, Ishii M, Brosnihan KB, Umemura S. Angiotensin (1-7) potentiates bradykinin-induced vasodilatation in man. J Hypertens. 2001;19(11):2001-2009.

Almeida AP, Frábregas BC, Madureira MM, Santos RJS, Campagnole-Santos MJ, Santos RAS. Angiotensin-(1-7) potentiates the coronary vasodilatory effect of bradykinin in the isolated rat heart. BRAZ J MED BIOL RES. 2000;33:709-713.

Santos RA, Campagnole-Santos MJ, Andrade SP. Angiotensin-(1-7): an update. Regul Pept. 2000;91(1-3):45-62.

van der Wouden EA, Henning RH, Deelman LE, Roks AJ, Boomsma F, de Zeeuw D. Does angiotensin (1-7) contribute to the antiproteinuric effect of ACE-inhibitors? J Renin Angiotensin Aldosterone Syst. 2005;6(2):96-101.

Velkoska E, Dean RG, Griggs K, Burchill L, Burrell LM. Angiotensin-(1-7) infusion is associated with increased blood pressure and adverse cardiac remodelling in rats with subtotal nephrectomy. Clin Sci (Lond). 2011;120(8):335-345.

Pinheiro SVB, Ferreira AJ, Kitten GT, da Silveira KD, da Silva DA, Santos SHS, et al. Genetic deletion of the angiotensin-(1-7) receptor Mas leads to glomerular hyperfiltration and microalbuminuria. Kidney Int. 2009;75(11): 1184-1193.

da Silveira KD, Bosco KSP, Diniz LR, Carmona AK, Cassali GD, Bruna-Romero O, et al. ACE2-angiotensin-(1-7)-Mas axis in renal ischaemia/reperfusion injury in rats. Clin Sci (Lond). 2010;119(9):385-394.

Pinheiro SV, Simoes e Silva AC, Sampaio WO, de Paula RD, Mendes EP, Bontempo ED, et al. Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney. Hypertension. 2004;44(4):490-496.

Matsusaka T, Asano T, Niimura F, Kinomura M, Shimizu A, Shintani A, et al. Angiotensin receptor blocker protection against podocyte-induced sclerosis is podocyte angiotensin II type 1 receptor-independent. Hypertension. 2010;55(4):967-973.

Naito T, Ma LJ, Yang H, Zuo Y, Tang Y, Han JY, et al. Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis. Am J Physiol Renal Physiol. 2010;298(3):F683-F691.


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