We investigated the involvement of peroxisome proliferator activated receptor-γ (PPAR-γ)/endothelial nitric oxide synthase (eNOS) pathway in estradiol mediated protection against ischemia reperfusion (I/R)-induced acute kidney injury (AKI) in rats. To induce AKI, rats underwent 40 min of bilateral renal ischemia followed by 24 h of reperfusion. I/R-induced kidney damage was quantified by measuring serum creatinine, creatinine clearance, urea nitrogen, uric acid, potassium, fractional excretion of sodium, microproteinuria, and renal oxidative stress (thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione). Hematoxylin eosin stain demonstrated renal histology, while renal expression of apoptotic markers (Bcl-2, Bax), PPAR-γ and eNOS were quantified by immunohistochemistry. Estradiol (1 mg/kg, i.p.) was administered 30 min before I/R in rats. In separate groups, PPAR-γ antagonist, BADGE (30 mg/kg, i.p.), and NOS inhibitor, l-NAME (20 mg/kg, i.p.) were administered prior to estradiol treatment, which was followed by I/R in rats. I/R caused significant renal damage as demonstrated by biochemical (serum/urine), renal oxidative stress and histological changes alongwith increased expression of Bax and decreased levels of Bcl-2, PPAR-γ and eNOS, which were prevented by estradiol. Pre-treatment with BADGE and l-NAME abolished estradiol mediated renoprotection. Notably, I/R + estradiol + BADGE group revealed decreased expression of PPAR-γ and eNOS in renal tissues. In I/R + estradiol + l-NAME group, eNOS expression was reduced while PPAR-γ levels remained unchanged. These results suggest that estradiol modulates PPAR-γ which consequently regulates eNOS expression in rat kidneys. We conclude that estradiol protects against I/R-induced AKI through PPAR-γ stimulated eNOS activation in rats.
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Ueda N, Kaushal GP, Shah SV (2000) Apoptotic mechanisms in acute renal failure. Am J Med 108:403–415
Hsu CY, Chertow GM, McCulloch CE, Fan D, Ordoñez JD, Go AS (2009) Non recovery of kidney function and death after acute on chronic renal failure. Clin J Am Soc Nephrol 4:891–898
Thadhani R, Pascual M, Bonventre JV (1996) Acute renal failure. N Engl J Med 334:1448–1460
Singh JP, Singh AP, Bhatti R (2014) Explicit role of peroxisome proliferator-activated receptor gamma in gallic acid-mediated protection against ischemia–reperfusion-induced acute kidney injury in rats. J Surg Res 187:631–639
Sivarajah A, Chatterjee PK, Patel NS, Todorovic Z, Hattori Y, Brown PA, Stewart KN, Mota-Filipe H, Cuzzocrea S, Thiemermann C (2003) Agonists of peroxisome-proliferator activated receptor-gamma reduce renal ischemia/reperfusion injury. Am J Nephrol 23:267–276
Dellamea BS, Leitão CB, Friedman R, Canani LH (2014) Nitric oxide system and diabetic nephropathy. Diabetol Metab Syndr 6:17
Kopkan L, Cervenka L (2009) Renal interactions of renin-angiotensin system, nitric oxide and superoxide anion: implications in the pathophysiology of salt-sensitivity and hypertension. Physiol Res 58:S55–S67
Rhoden EL, Rhoden CR, Lucas ML, Pereira-Lima L, Zettler C, Belló-Klein A (2002) The role of nitric oxide pathway in the renal ischemia–reperfusion injury in rats. Transpl Immunol 10:277–284
Chander V, Chopra K (2005) Renal protective effect of molsidomine and l-arginine in ischemia–reperfusion induced injury in rats. J Surg Res 128:132–139
Singh AP, Singh N, Singh Bedi PM (2016) Estrogen attenuates renal IRI through PPAR-γ agonism in rats. J Surg Res 203:324–330
Shibata Y, Takaoka M, Maekawa D, Kuwahara C, Matsumura Y (2004) Involvement of nitric oxide in the suppressive effect of 17β-estradiol on endothelin-1 over production in ischemic acute renal failure. J Cardiovasc Pharmacol 44:S459–S461
Singh AP, Singh N, Bedi PMS (2017) Estradiol mitigates ischemia reperfusion-induced acute renal failure through NMDA receptor antagonism in rats. Mol Cell Biochem 434:33–40
Calnek DS, Mazzella L, Roser S, Roman J, Hart CM (2003) Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 23:52–57
Polikandriotis JA, Mazzella LJ, Rupnow HL, Hart CM (2005) Peroxisome proliferator-activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor gamma-dependent mechanisms. Arterioscler Thromb Vasc Biol 25:1810–1816
Wang J, Yang K, Xu L, Zhang Y, Lai N, Jiang H, Zhang Y, Zhong N, Ran P, Lu W (2013) Sildenafil inhibits hypoxia-induced transient receptor potential canonical protein expression in pulmonary arterial smooth muscle via cGMP-PKG-PPARγ axis. Am J Respir Cell Mol Biol 49:231–240
Kuo KK, Wu BN, Chiu EY, Tseng CJ, Yeh JL, Liu CP, Chai CY, Chen IJ (2013) NO donor KMUP-1 improves hepatic ischemia–reperfusion and hypoxic cell injury by inhibiting oxidative stress and pro-inflammatory signaling. Int J Immunopathol Pharmacol 26:93–106
Singh AP, Singh N, Bedi PM (2016) Pioglitazone ameliorates renal ischemia reperfusion injury through NMDA receptor antagonism in rats. Mol Cell Biochem 417:111–118
Mao Z, Ong AC (2009) Peroxisome proliferator-activated receptor gamma agonists in kidney disease-future promise, present fears. Nephron Clin Pract 112:C230–C241
Pereira MG, Câmara NO, Campaholle G, Cenedeze MA, de Paula Antunes Teixeira V, dos Reis MA, Pacheco-Silva A (2006) Pioglitazone limits cyclosporine nephrotoxicity in rats. Int Immunopharmacol 6:1943–1951
Kapil A, Singh JP, Kaur T, Singh B, Singh AP (2013) Involvement of peroxisome proliferator-activated receptor gamma in vitamin D-mediated protection against acute kidney injury in rats. J Surg Res 185:774–783
Mohey V, Singh M, Puri N, Kaur T, Pathak D, Singh AP (2016) Sildenafil obviates ischemia–reperfusion injury-induced acute kidney injury through peroxisome proliferator-activated receptor γ agonism in rats. J Surg Res 201:69–75
Gabbai FB (2001) Effects of nitric oxide synthase blockers on renal function. Nephrol Dial Transplant 16:10–13
Lee J (2008) Nitric oxide in the kidney: its physiological role and pathophysiological implications. Electrolyte Blood Press 6:27–34
Sikorski EM, Hock T, Hill-Kapturczak N, Agarwal A (2004) The story so far: molecular regulation of the heme oxygenase-1 gene in renal injury. Am J Physiol Renal Physiol 286:F425–F441
Mahfoudh-Boussaid A, Hadj Ayed Tka K, Zaouali MA, Roselló-Catafau J, Ben Abdennebi H (2014) Effects of trimetazidine on the Akt/eNOS signaling pathway and oxidative stress in an in vivo rat model of renal ischemia–reperfusion. Ren Fail 36:1436–1442
Rodriguez-Peña A, Garcia-Criado FJ, Eleno N, Arevalo M, Lopez-Novoa JM (2004) Intrarenal administration of molsidomine, a molecule releasing nitric oxide, reduces renal ischemia–reperfusion injury in rats. Am J Transplant 4:1605–1613
Wever R, Boer P, Hijmering M, Stroes E, Verhaar M, Kastelein J, Versluis K, Lagerwerf F, van Rijn H, Koomans H, Rabelink T (1999) Nitric oxide production is reduced in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 19:1168–1172
Bonomini M, Pandolfi A, Di Pietro N, Sirolli V, Giardinelli A, Consoli A, Amoroso L, Gizzi F, De Lutiis MA, Felaco M (2005) Adherence of uremic erythrocytes to vascular endothelium decreases endothelial nitric oxide synthase expression. Kidney Int 67:1899–1906
Rusai K, Fekete A, Szebeni B, Vannay A, Bokodi G, Müller V, Viklicky O, Bloudickova S, Rajnoch J, Heemann U, Reusz G, Szabó A, Tulassay T, Szabó AJ (2008) Effect of inhibition of neuronal nitric oxide synthase and l-arginine supplementation on renal ischaemia-reperfusion injury and the renal nitric oxide system. Clin Exp Pharmacol Physiol 35:1183–1189
Valdivielso JM, Crespo C, Alonso JR, Martínez-Salgado C, Eleno N, Arévalo M, Pérez-Barriocanal F, López-Novoa JM (2001) Renal ischemia in the rat stimulates glomerular nitric oxide synthesis. Am J Physiol Regul Integr Comp Physiol 280:R771–R779
Cho DH, Choi YJ, Jo SA, Jo I (2004) Nitric oxide production and regulation of endothelial nitric-oxide synthase phosphorylation by prolonged treatment with troglitazone: evidence for involvement of peroxisome proliferator-activated receptor (PPAR) gamma-dependent and PPAR gamma-independent signaling pathways. J Biol Chem 279:2499–2506
Betz B, Schneider R, Kress T, Schick MA, Wanner C, Sauvant C (2012) Rosiglitazone affects nitric oxide synthases and improves renal outcome in a rat model of severe ischemia/reperfusion injury. PPAR Res. https://doi.org/10.1155/2012/219319
Balakumar P, Kathuria S (2012) Submaximal PPARγ activation and endothelial dysfunction: new perspectives for the management of cardiovascular disorders. Br J Pharmacol 166:1981–1992
Hong TY, Guh JY, Wu BN, Chai CY, Huang HT, Chen IJ (2014) KMUP-l protects kidney from streptozotocin-induced proinflammation in early diabetic nephropathy by restoring eNOS/PPAR-γ and inhibiting MMP-9. Eur J Inflamm 12:89–100
Brar R, Singh JP, Kaur T, Arora S, Singh AP (2014) Role of GABAergic activity of sodium valproate against ischemia–reperfusion-induced acute kidney injury in rats. Naunyn Schmiedebergs Arch Pharmacol 387:143–151
Nose K (2000) Role of reactive oxygen species in the regulation of physiological functions. Biol Pharm Bull 23:897–903
Sinha K, Das J, Pal PB, Sil PC (2013) Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol 87:1157–1180
Li Y, Zhong D, Lei L, Jia Y, Zhou H, Yang B (2015) Propofol prevents renal ischemia–reperfusion injury via inhibiting the oxidative stress pathways. Cell Physiol Biochem 37:14–26
Havasi A, Borkan SC (2011) Apoptosis and acute kidney injury. Kidney Int 80:29–40
Cheng H, Wang H, Fan X, Paueksakon P, Harris RC (2012) Improvement of endothelial nitric oxide synthase activity retards the progression of diabetic nephropathy in db/db mice. Kidney Int 82:1176–1183
Doi S, Masaki T, Arakawa T, Takahashi S, Kawai T, Nakashima A, Naito T, Kohno N, Yorioka N (2007) Protective effects of peroxisome proliferator-activated receptor gamma ligand on apoptosis and hepatocyte growth factor induction in renal ischemia–reperfusion injury. Transplantation 84:207–213
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Singh, A.P., Singh, N., Pathak, D. et al. Estradiol attenuates ischemia reperfusion-induced acute kidney injury through PPAR-γ stimulated eNOS activation in rats. Mol Cell Biochem 453, 1–9 (2019). https://doi.org/10.1007/s11010-018-3427-4
- Ischemia reperfusion
- Nitric oxide