Estradiol attenuates ischemia reperfusion-induced acute kidney injury through PPAR-γ stimulated eNOS activation in rats

Abstract

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Ueda N, Kaushal GP, Shah SV (2000) Apoptotic mechanisms in acute renal failure. Am J Med 108:403–415

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    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

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Thadhani R, Pascual M, Bonventre JV (1996) Acute renal failure. N Engl J Med 334:1448–1460

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    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

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    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

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Dellamea BS, Leitão CB, Friedman R, Canani LH (2014) Nitric oxide system and diabetic nephropathy. Diabetol Metab Syndr 6:17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    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

    CAS  PubMed  Google Scholar 

  8. 8.

    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

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    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

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Singh AP, Singh N, Singh Bedi PM (2016) Estrogen attenuates renal IRI through PPAR-γ agonism in rats. J Surg Res 203:324–330

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    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

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    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

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    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

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    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

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    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

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    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

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Mao Z, Ong AC (2009) Peroxisome proliferator-activated receptor gamma agonists in kidney disease-future promise, present fears. Nephron Clin Pract 112:C230–C241

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    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

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    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

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    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

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Gabbai FB (2001) Effects of nitric oxide synthase blockers on renal function. Nephrol Dial Transplant 16:10–13

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Lee J (2008) Nitric oxide in the kidney: its physiological role and pathophysiological implications. Electrolyte Blood Press 6:27–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    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

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    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

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    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

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    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

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    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

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    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

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    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

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    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

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    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

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    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

    Article  CAS  Google Scholar 

  35. 35.

    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

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Nose K (2000) Role of reactive oxygen species in the regulation of physiological functions. Biol Pharm Bull 23:897–903

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    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

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    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

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Havasi A, Borkan SC (2011) Apoptosis and acute kidney injury. Kidney Int 80:29–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    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

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Preet Mohinder Singh Bedi.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • Kidney
  • Ischemia reperfusion
  • Nitric oxide
  • PPAR-γ
  • eNOS
  • Estradiol