The Protective Effect of γ-aminobutyric Acid on Kidney Injury Induced by Renal Ischemia-reperfusion in Ovariectomized Estradiol-treated Rats

Nahid Talebi, Mehdi Nematbakhsh, Ramesh Monajemi, Safoora Mazaheri, Ardeshir Talebi, Marzieh Vafapour, Nahid Talebi, Mehdi Nematbakhsh, Ramesh Monajemi, Safoora Mazaheri, Ardeshir Talebi, Marzieh Vafapour

Abstract

Background: Renal ischemia-reperfusion injury (IRI) is one of the most important causes of kidney injury, which is possibly gender-related. This study was designed to investigate the role of γ-aminobutyric acid (GABA) against IRI in ovariectomized estradiol-treated rats.

Methods: Thirty-five ovariectomized Wistar rats were used in six experimental groups. The first three groups did not subject to estradiol treatment and assigned as sham-operated, control, and GABA-treated groups. GABA (50 μmol/kg) and saline were injected in the treated and control groups 30 min before the surgery, respectively. The second three groups received the same treatments but received estradiol valerate (500 μg/kg, intramuscularly) 3 days prior to the surgery. The IRI was induced in the control and treated groups by clamping the renal artery for 45 min and then 24 h of reperfusion. All animals were sacrificed for the measurements.

Results: The serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score significantly increased in the IRI rats (P < 0.05). GABA significantly decreased the aforementioned parameters (P < 0.05). The uterus weight increased significantly in rats that received estradiol (P < 0.05). Serum and kidney levels of nitrite (nitric oxide metabolite) did not alter significantly. Serum level of malondialdehyde increased significantly in the ovariectomized rats exposed to IRI (P < 0.05).

Conclusions: It seems that GABA improved IRI in ovariectomized rats. Estradiol was also nephroprotective against IRI. However, co-administration of estradiol and GABA could not protect the kidney against IRI.

Keywords: Estradiol; ovariectomized rats; renal ischemia-reperfusion; γ-aminobutyric acid.

Conflict of interest statement

Conflict of Interest: None declared.

Figures

Figure 1
Figure 1
Serum levels of blood urea nitrogen (BUN) and creatinine (Cr); kidney weight (KW); body weight change (ΔBW), kidney tissue damage score (KTDS), and uterus weight (UW). The *, #, &, and @ indicate significant difference from the OVIG, OVI, OVE, and OV groups, respectively
Figure 2
Figure 2
Images of kidney tissue (magnification ×400). OV = Ovariectomized + Saline, OVI = Ovariectomized + Ischemia, OVIG = Ovariectomized + Ischemia + GABA, OVE = Ovariectomized + Estradiol, OVEI = Ovariectomized + Estradiol + Ischemia, OVEIG = Ovariectomized + Estradiol + Ischemia+ GABA. Higher tissue damage was observed in the OVI group

References

    1. Sharfuddin AA, Molitoris BA. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol. 2011;7:189–200.
    1. Hutchens MP, Dunlap J, Hurn PD, Jarnberg PO. Renal ischemia: Does sex matter? Anesth Analg. 2008;107:239–49.
    1. Baumgarten M, Gehr T. Chronic kidney disease: Detection and evaluation. Am Fam Physician. 2011;84:1138–48.
    1. Li X, Hassoun HT, Santora R, Rabb H. Organ crosstalk: The role of the kidney. Curr Opin Crit Care. 2009;15:481–7.
    1. Gu J, Sun P, Zhao H, Watts HR, Sanders RD, Terrando N, et al. Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice. Crit Care. 2011;15:R153.
    1. Karaman A, Turkmen E, Gursul C, Tas E, Fadillioglu E. Prevention of renal ischemia/reperfusion-induced injury in rats by leflunomide. Int J Urol. 2006;13:1434–41.
    1. Singh D, Chander V, Chopra K. Protective effect of catechin on ischemia-reperfusion-induced renal injury in rats. Pharmacol Rep. 2005;57:70–6.
    1. Lin F, Cordes K, Li L, Hood L, Couser WG, Shankland SJ, et al. Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice. J Am Soc Nephrol. 2003;14:1188–99.
    1. Daemen MA, van ’t Veer C, Denecker G, Heemskerk VH, Wolfs TG, Clauss M, et al. Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation. J Clin Invest. 1999;104:541–9.
    1. Kobuchi S, Tanaka R, Shintani T, Suzuki R, Tsutsui H, Ohkita M, et al. Mechanisms underlying the renoprotective effect of GABA against ischemia/reperfusion-induced renal injury in rats. J Pharmacol Exp Ther. 2011;338:767–74.
    1. Kim HY, Yokozawa T, Nakagawa T, Sasaki S. Protective effect of gamma-aminobutyric acid against glycerol-induced acute renal failure in rats. Food Chem Toxicol. 2004;42:2009–14.
    1. Brar R, Singh JP, Kaur T, Arora S, Singh AP. Role of GABAergic activity of sodium valproate against ischemia-reperfusion-induced acute kidney injury in rats. Naunyn Schmiedebergs Arch Pharmacol. 2014;387:143–51.
    1. Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H. GABA and GABA receptors in the central nervous system and other organs. Int Rev Cytol. 2002;213:1–47.
    1. Zhang K, Patel KP. Effect of nitric oxide within the paraventricular nucleus on renal sympathetic nerve discharge: Role of GABA. Am J Physiol. 1998;275:R728–34.
    1. Vink EE, Blankestijn PJ. Evidence and consequences of the central role of the kidneys in the pathophysiology of sympathetic hyperactivity. Frontiers in Physiology. 2012;3:29.
    1. Kobuchi S, Shintani T, Sugiura T, Tanaka R, Suzuki R, Tsutsui H, et al. Renoprotective effects of gamma-aminobutyric acid on ischemia/reperfusion-induced renal injury in rats. Eur J Pharmacol. 2009;623:113–8.
    1. Zoubina EV, Smith PG. Sympathetic hyperinnervation of the uterus in the estrogen receptor alpha knock-out mouse. Neuroscience. 2001;103:237–44.
    1. Hutchens MP, Fujiyoshi T, Komers R, Herson PS, Anderson S. Estrogen protects renal endothelial barrier function from ischemia-reperfusion in vitro and in vivo. Am J Physiol Renal Physiol. 2012;303:F377–85.
    1. Yanes LL, Sartori-Valinotti JC, Reckelhoff JF. Sex steroids and renal disease: Lessons from animal studies. Hypertension. 2008;51:976–81.
    1. Park KM, Kim JI, Ahn Y, Bonventre AJ, Bonventre JV. Testosterone is responsible for enhanced susceptibility of males to ischemic renal injury. J Biol Chem. 2004;279:52282–92.
    1. Moeini M, Nematbakhsh M, Fazilati M, Talebi A, Pilehvarian AA, Azarkish F, et al. Protective role of recombinant human erythropoietin in kidney and lung injury following renal bilateral ischemia-reperfusion in rat model. Int J Prev Med. 2013;4:648–55.
    1. Azarkish F, Nematbakhsh M, Fazilati M, Talebi A, Pilehvarian AA, Pezeshki Z, et al. N-acetylcysteine prevents kidney and lung disturbances in renal ischemia/reperfusion injury in rat. Int J Prev Med. 2013;4:1139–46.
    1. Basile DP. The endothelial cell in ischemic acute kidney injury: Implications for acute and chronic function. Kidney Int. 2007;72:151–6.
    1. Haase M, Bellomo R, Haase-Fielitz A. Novel biomarkers, oxidative stress, and the role of labile iron toxicity in cardiopulmonary bypass-associated acute kidney injury. J Am Coll Cardiol. 2010;55:2024–33.
    1. Greene EL, Paller MS. Oxygen free radicals in acute renal failure. Miner Electrolyte Metab. 1991;17:124–32.
    1. Li C, Jackson RM. Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol. 2002;282:C227–41.
    1. Coresh J, Astor BC, McQuillan G, Kusek J, Greene T, Van Lente F, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis. 2002;39:920–9.
    1. Matsushima H, Yonemura K, Ohishi K, Hishida A. The role of oxygen free radicals in cisplatin-induced acute renal failure in rats. J Lab Clin Med. 1998;131:518–26.
    1. Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: Definitions, diagnosis, pathogenesis, and therapy. J Clin Invest. 2004;114:5–14.
    1. Hutchens MP, Nakano T, Kosaka Y, Dunlap J, Zhang W, Herson PS, et al. Estrogen is renoprotective via a nonreceptor-dependent mechanism after cardiac arrest in vivo. Anesthesiology. 2010;112:395–405.
    1. Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol. 2003;14:2199–210.
    1. Chang CC, Kuan TC, Hsieh YY, Ho YJ, Sun YL, Lin CS. Effects of diosgenin on myometrial matrix metalloproteinase-2 and -9 activity and expression in ovariectomized rats. Int J Biol Sci. 2011;7:837–47.
    1. Papaconstantinou AD, Umbreit TH, Fisher BR, Goering PL, Lappas NT, Brown KM. Bisphenol A-induced increase in uterine weight and alterations in uterine morphology in ovariectomized B6C3F1 mice: Role of the estrogen receptor. Toxicol Sci. 2000;56:332–9.
    1. Del Rio D, Stewart AJ, Pellegrini N. A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Dis. 2005;15:316–28.
    1. Paller MS, Neumann TV. Reactive oxygen species and rat renal epithelial cells during hypoxia and reoxygenation. Kidney Int. 1991;40:1041–9.
    1. Deng Y, Xu L, Zeng X, Li Z, Qin B, He N. New perspective of GABA as an inhibitor of formation of advanced lipoxidation end-products: It's interaction with malondiadehyde. J Biomed Nanotechnol. 2010;6:318–24.
    1. Shen SQ, Zhang Y, Xiong CL. The protective effects of 17beta-estradiol on hepatic ischemia-reperfusion injury in rat model, associated with regulation of heat-shock protein expression. J Surg Res. 2007;140:67–76.
    1. Bolli R. Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: An overview of a decade of research. J Mol Cell Cardiol. 2001;33:1897–918.
    1. Node K, Kitakaze M, Kosaka H, Minamino T, Funaya H, Hori M. Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: Role of nitric oxide and calcium-activated potassium channels. Circulation. 1997;96:1953–63.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere