Kidney Research and Clinical Practice

Korean Society of Nephrology (대한신장학회)
권호 표지

Does HSP70 Induced by Amphetamine Prevent Renal Ischemia/Reperfusion Injury in Rat?

흰쥐에서 허혈성 재관류 손상에 대한 Amphetamine 전처치의 신보호 효과가 Heat Shock Protein에 의한 것인가?

Jo, Young-Il;Na, Heung-Sik;Back, Seung-Keun;Cho, Seung-Che;Kim, Kyo-Soon;Choi, Young-Sook;Song, Jong-Oh
조영일;나흥식;백승근;조승제;김교순;최영숙;송종오

  • Published : 20040000
⟨ Previous Next ⟩

Abstract

Background:Heat shock proteins (HSPs) induced by variable kinds of stress produce tolerance to a variety of adverse conditions. However, the protective effect of HSP on ischemia/reperfusion injury (I/R injury) of kidney in vivo remains unclear. The present study was designed to evaluate whether HSP70 induced by hyperthermic preconditioning had renoprotective effect on I/R injury of the kidney in vivo. Methods:82 Sprague-Dawley male rats were used. Animals in control group (n=24) were subjected to bilateral occlusion of renal pedicles for 30 or 60 minutes followed by 24-hour reperfusion. In amphetamine (Amp, n=18) and quercetin (Q, n=16) group, amphetamine sulfate, a sympathomimetic drug which can elevate the body temperature as a result of enhanced endogenous lipolysis, and quercetin, a biflavonoid which inhibit the expression of HSP, were injected 4 hours prior to renal ischemia, respectively. In quercetin-amphetamine (QAmp, n=7) group, quercetin was injected 1 hour before administration of amphetamine. AA (n=8) or QQ (n=9) group was identical to Amp or Q group except that sham operation was performed instead of ischemic insult. In all groups, animals were sacrificed prior to or 24 hours after I/R injury. HSP70 induction was confirmed by immunohistochemistry. To assess the I/R injury of kidney, BUN, Cr, histopathologic change of tubular cell and HSP70 expression were evaluated. Results:In Amp group, an increase of BUN and Cr were significantly lower than other groups and less severe renal tubular injury was also observed. In addition, HSP70 was strongly expressed in Amp group, whereas HSP70 was weakly expressed in control group and not expressed in QAmp and Q group. There were no differences in the functional and histologic injuries of kidney after I/R injury between AA, QQ and control group. Conclusion:These data demonstrate that the renoprotective effect by amphetamine preconditioning to I/R injury is linked with the expression of HSP70.

목 적:In vivo에서 heat shock protein (HSP)이 허혈성 재관류 손상 (I/R injury)에 대한 신보호 효과를 가지는지에 대해서는 상반된 연구 결과들이 보고되고 있다. 저자들은 발열작용을 하는 암페타민과 HSP의 발현을 억제하는 작용이 있는 quercetin을 이용하여 in vivo에서 열전처치가 신장의 I/R injury에 대해 어떤 효과를 나타내는지, 그리고 신보호 효과가 있다면 그것이 HSP의 발현에 의한 것인지를 규명하고자 하였다. 방 법:Sprague-Dawley rat를 대상으로 암페타민 혹은 quercetin으로 전처치 후에 양측 신동맥을 30분 혹은 60분 동안 결찰하고 24시간 동안 재관류시킨 다음 희생시켜 BUN/Cr, histopathologic score 및 HSP70의 발현을 조사하기 위한 immunohistochemistry 검사를 시행하였다. 결 과:신동맥을 결찰하기 전에 암페타민 전처치를 시행한 군에서는 재관류 후의 BUN, Cr, histopathologic score가 대조군에 비해 유의하게 낮았다. 반면에, 암페타민 전처치 전에 quercetin을 투여한 군이나 quercetin만을 단독으로 투여한 군에서는 대조군과 유의한 차이를 나타내지 않았다. HSP70은 암페타민 전처치를 시행한 군에서 발현이 증가하였으나, 나머지 군에서는 HSP70이 발현되지 않거나 미미하였다. 결 론:흰쥐에서 암페타민 전처치는 신장의 I/R injury에 대해 신보호 효과를 나타내었고, 이러한 효과는 암페타민 전처치로 생성된 HSP70과 관련이 있었다.

Keywords

References

  1. Tilney NL, Paz D, Ames J, Gasser M, Laskowski I, Hancock WW:Ischemia-reperfusion injury. Transplant Proc 33:843-844, 2001
  2. Yang CW, Ahn HJ, Han HJ, Kim WY, Li C, Shin MJ, Kim SK, Park JH, Kim YS, Moon IS, Bang BK:Pharmacological preconditioning with low-dose cyclosporine or FK506 reduces subsequent ischemia/reperfusion injury in rat kidney. Transplantation 72:1753-1759, 2001
  3. Troppmann C, Gillingham KJ, Benedetti E, Almond PS, Gruessner RW, Najarian JS, Matas AJ:Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. The multivariate analysis. Transplantation 15:962-968, 1995
  4. Pagtalunan ME, Olson JL, Tilney NL, Meyer TW:Late consequences of acute ischemic injury to a solitary kidney. J Am Soc Nephrol 10:366- 373, 1999
  5. Lee HT, Emala CW:Protective effects of renal ischemic preconditioning and adenosine pretreatment:role of A1 and A3 receptors. Am J Physiol Renal Physiol 278:380-387, 2000
  6. Zhou W, Farrar CA, Abe K, Pratt JR, Marsh JE, Wang Y, Stahl GL, Sacks SH:Predominant role for C5b-9 in renal ischemia/reperfusion injury. J Clin Invest 105:1363-1371, 2000
  7. Javadpour M, Kelly CJ, Chen G, Stokes K, Leahy A, Bouchier-Hayes DJ:Thermotolerance induces heat shock protein 72 expression and protects against ischaemia-reperfusion-induced lung injury. Br J Surg 85:943-946, 1998
  8. Maulik N, Engelman RM, Wei Z, Liu X, Rousou JA, Flack JE, Deaton DW, Das DK:Drug- induced heat-shock preconditioning improves postischemic ventricular recovery after cardiopulmonary bypass. Circulation 92:381-388, 1995
  9. William ES, Ransom R, Harris RC, Welsh MJ, Lutsch G, Benndorf R:Ischemic acute renal failure induces differential expression of small heat shock proteins. J Am Soc Nephrol 11:211-221, 2000
  10. Kelly KJ, Baird NR, Greene AL:Induction of stress response proteins and experimental renal ischemia/reperfusion. Kidney Int 59:1798-1802, 2001
  11. Pockley AG:Heat shock proteins, anti-heat shock protein reactivity and allograft rejection. Transplantation 71:1503-1507, 2001
  12. Meldrum KK, Meldrum DR, Sezen SF, Crone JK, Burnett AL:Heat shock prevents simulated ischemia-induced apoptosis in renal tubular cells via a PKC-dependent mechanism. Am J Physiol Regul Integr Comp Physiol 281:359-364, 2001
  13. Meldrum KK, Burnett AL, Meng X, Misseri R, Shaw MB, Gearhart JP, Meldrum DR:Liposomal delivery of heat shock protein 72 into renal tubular cells blocks nuclear factor-kappaB activation, tumor necrosis factor-alpha production, and subsequent ischemia-induced apoptosis. Circ Res 92:293-299, 2003
  14. Park KM, Chen A, Bonventre JV:Prevention of kidney ischemia/reperfusion-induced functional injury and JNK, p38, and MAPK kinase activation by remote ischemic pretreatment. J Biol Chem 276:11870-11876, 2001
  15. Joannidis M, Cantley LG, Spokes K, Medina R, Pullman J, Rosen S, Epstein FH:Induction of heat-shock proteins does not prevent renal tubular injury following ischemia. Kidney Int 47: 1752-1759, 1995
  16. Islam CF, Mathie RT, Dinneen MD, Kiely EA, Peters AM, Grace PA:Ischaemia-reperfusion injury in the rat kidney:the effect of preconditioning. Br J Urol 79:842-847, 1997
  17. Perdrizet GA, Kaneko H, Buckley TM, Fishman MS, Pleau M, Bow L, Schweizer RT:Heat shock and recovery protects renal allografts from warm ischemic injury and enhances HSP72 production. Transplant Proc 25:1670-1673, 1993
  18. Zager RA, Iwata M, Burkhart KM, Schimpf BA:Post-ischemic acute renal failure protects proximal tubules from O_2 deprivation injury, possibly by inducing uremia. Kidney Int 45:1760-1768, 1994
  19. Birk OS, Gur SL, Elias D, Margalit R, Mor F, Carmi P, Bockova J, Altmann DM, Cohen IR:The 60-kDa heat shock protein modulates allograft rejection. Proc Natl Acad Sci 96:5159- 5163, 1999
  20. Redaelli CA, Tien YH, Kubulus D, Mazzucchelli L, Schilling MK, Wagner AC:Hyperthermia preconditioning induces renal heat shock protein expression, improves cold ischemia tolerance, kidney graft function and survival in rats. Nephron 90:489-497, 2002
  21. Redaelli CA, Wagner M, Kulli C, Tian YH, Kubulus D, Mazzucchelli L, Wagner AC, Schilling MK:Hyperthermia-induced HSP expression correlates with improved rat renal isograft viability and survival in kidneys harvested from non-heart- beating donors. Transpl Int 14:351-360, 2001
  22. Kelly KJ, Williams WWJr, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC, Bonventre JV:Intercellular adhesion molecule-1 deficient mice are protected against ischemic renal injury. J Clin Invest 97:1056-1063, 1996
  23. Hsu SM, Raine L:Protein A, avidin, and biotin in immunohistochemistry. J Histochem Cytochem 29:1349-1353, 1981
  24. Trieb K, Dirnhofer S, Krumbock N, Blahovec H, Sgonc R, Margreiter R, Feichtinger H:Heat shock protein expression in the transplanted human kidney. Transpl Int 14:281-286, 2001
  25. Beck FX, Neuhofer W, Muller E:Molecular chaperones in the kidney:distribution, putative roles, and regulation. Am J Physiol Renal Physiol 279:203-215, 2000
  26. Cochrane J, Williams BT, Banerjee A, Harken AH, Burke TJ, Cairns CB, Shapiro JI:Ischemic preconditioning attenuates functional, metabolic, and morphologic injury from ischemic acute renal failure in the rat. Ren Fail 21:135-145, 1999
  27. Chen HC, Guh JY, Tsai JH, Lai YH:Induction of heat shock protein 70 protects mesangial cells against oxidative injury. Kidney Int 56:1270- 1273, 1999
  28. Maulik N, Wei Z, Liu X, Engelman RM, Rousou JA, Das DK:Improved postischemic ventricular functional recovery by amphetamine is linked with its ability to induce heat shock. Mol Cell Biochem 137:17-24, 1994
  29. Tsukimi Y, Fujishita T, Nakajima K, Okabe S:Effect of rebamipide on cell death induced by combined treatment of mild heat shock and quercetin in RGM-1 cells:a role for HSP70 induction. Pharmacology 64:28-35, 2002
  30. Shoskes DA:Effect of bioflavonoids quercetin and curcumin on ischemic renal injury:a new class of renoprotective agents. Transplantation 27:147-152, 1998
  31. Jones EA, Shahed A, Shoskes DA:Modulation of apoptotic and inflammatory genes by bioflavonoids and angiotensin II inhibition in ureteral obstruction. Urology 56:346-351, 2000
  32. Shahed AR, Jones E, Shoskes D:Quercetin and curcumin up-regulate antioxidant gene expression in rat kidney after ureteral obstruction or ischemia/reperfusion injury. Transplant Proc 33: 2988, 2001