PHARMASPIRE - Volume 11, Issue 4, October - December, 2019
Pages: 117-123
Date of Publication: 14-Jun-2022
Print Article
Download XML Download PDF
Effects of pre-ischemic prolyl-hydroxylase inhibitor on long-term renal functions in rats
Author: Gaaminepreet Singh, Rimpi Arora, Pawan Krishan
Category: Pharmaceutics
Abstract:
Background: Ischemia leads to acute kidney injury (AKI) and associated with adverse hospital outcomes. It is known that AKI resolves in few days, but the progressive kidney disease does not halt. Induction of ischemia-reperfusion (I/R) injury results in oxygen metabolism defects resulting in hypoxia, which activates fibrogenic responses. The hypoxia inducible factors (HIFs) system comprising of HIF-1α and HIF-1β subunits is degraded by prolyl-hydroxylase (PHD) enzyme. Several evidences have suggested that inhibition of HIFs degradation prevents renal I/R induced AKI in rodents. However, the effects of HIF pre-induction on renal I/R induced chronic kidney disease (CKD) in rodents has not been investigated. Materials and Methods: Bilateral renal I/R injury was performed by clamping both renal pedicels for 45 min. Modulation of HIFs was done by administering PHD inhibitor cobaltous chloride prior to I/R. CKD was evaluated by proteinuria, oxidative stress, HIF-1α protein levels and histological studies. Results: Renal I/R injury induced AKI as indicated by elevated serum creatinine levels post 1 day. Various CKD features such as proteinuria, reduced catalase activity, glomerular hypertrophy, glomerulosclerosis, fibrosis were evidenced 90 days post I/R injury. Pre-treatment with PHD inhibitor reduced the incidence of AKI in I/R rats. Besides up-regulation of renal HIF-1α protein levels after 90 days, development of CKD was not retarded in pre-treated I/R rats. Conclusion: Thus, we conclude that early HIF modulation is insufficient in attenuating I/R induced CKD in rats.
Keywords: Gaaminepreet Singh, Rimpi Arora, Pawan Krishan
References:
1. Diesase K. Improving global outcomes (KDIGO) acute kidney injury work group: KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012;2:1-38.
2. Zhang WR, Garg AX, Coca SG, Devereaux PJ, Eikelboom J, Kavsak P, et al. Plasma IL-6 and IL-10 concentrations predict AKI and long-term mortality in adults after cardiac surgery. J Am Soc Nephrol 2015;26:3123-32.
3. Khatri M, Himmelfarb J, Adams D, Becker K, Longstreth WT, Tirschwell DL. Acute kidney injury is associated with increased hospital mortality after stroke. J Stroke Cerebrovasc Dis 2014;23:25-30.
4. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39:930-6.
5. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS): A prospective study. JAMA 1995;273:117-23.
6. Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury. Clin Immunol 2009;130:41-50.
7. Sharfuddin AA, Molitoris BA. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 2011;7:189-200.
8. Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol 2001;281:F887-99.
9. Basile DP. Rarefaction of peritubular capillaries following ischemic acute renal failure: A potential factor predisposing to progressive nephropathy. Curr Opin Nephrol Hypertens 2004;13:1-7.
10. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: A systematic review and meta-analysis. Kidney Int 2012;81:442-8.
11. Barrera-Chimal J, Pérez-Villalva R, Rodríguez-Romo R, Reyna J, Uribe N, Gamba G, et al. Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury. Kidney Int 2013;83:93-103.
12. Haase VH. Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol 2006;291:F271-81.
13. Maxwell P. HIF-1: An oxygen response system with special relevance to the kidney. J Am Soc Nephrol 2003;14:2712-22.
14. Hill P, Shukla D, Tran MG, Aragones J, Cook HT, Carmeliet P, et al. Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemiareperfusion injury. Am Soc Nephrol 2008;19:39-46.
15. Bernhardt WM, Câmpean V, Kany S, Jürgensen JS, Weidemann A, Warnecke C, et al. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J Am Soc Nephrol 2006;17:1970-8.
16. Wang Z, Schley G, Türkoglu G, Burzlaff N, Amann KU, Willam C, et al. The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment. Nephrol Dial Transplant 2011;27:929-36.
17. Rodríguez-Romo R., Benítez K., Barrera-Chimal J, Pérez-Villalva R, Gómez A, Aguilar-León D, et al. AT1 receptor antagonism before ischemia prevents the transition of acute kidney injury to chronic kidney disease. Kidney Int 2016;89:363-73.
18. Nordquist L, Friederich-Persson M, Fasching A, Liss P, Shoji K, Nangaku M, et al. Activation of hypoxia-inducible factors prevents diabetic nephropathy. J Am Soc Nephrol 2015;26:328-38.
19. Boyne AF, Ellman GL. A methodology for analysis of tissue sulfhydryl components. Anal Biochem 1972;46:639-53.
20. Gwinner W, Deters-Evers U, Brandes RP, Kubat B, Koch KM, Pape M, et al. Antioxidant-oxidant balance in the glomerulus and proximal tubule of the rat kidney. J Physiol 1998;509:599-606.
21. Schacterle GR, Pollack RL. A simplified method for the quantitative assay of small amounts of protein in biologic material. Anal Biochem 1973;51:654-5.
22. Agarwal SK. Sethi S, Dinda AK. Basics of kidney biopsy: A nephrologist’s perspective. Indian J Nephrol 2013;23:243.
23. Junqueira LC, Bignolas G, Brentani RR. Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J 1979;11:447-55.
24. Singh G, Krishan P. Cobalt treatment does not prevent glomerular morphological alterations in Type 1 diabetic rats. Naunyn Schmiedebergs Arch Pharmacol 2018;391:933-44.
25. Cerda J, Lameire N, Eggers P, Pannu N, Uchino S, Wang H, et al. Epidemiology of acute kidney injury. J Am Soc Nephrol 2008;3:881-6. 26. Ishani A, Xue JL, Himmelfarb J, Eggers PW, Kimmel PL, Molitoris BA, et al. Acute kidney injury increases risk of ESRD among elderly. J Am Soc Nephrol 2009;20:223-8.
27. Tanaka S, Tanaka T, Nangaku M. Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol 2014;307:F1187-95.
28. Matsumoto M, Makino Y, Tanaka T. Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats. J Am Soc Nephrol 2003;14:1825-32.
29. Barrera-Chimal J, Rocha L, Amador-Martínez I, Pérez-Villalva R, González R, Cortés-González C, et al. Delayed spironolactone administration prevents the transition from acute kidney injury to chronic kidney disease through improving renal inflammation. Nephrol Dial Transplant 2018;
30. Fine L, Orphanides C, Norman JT. Progressive renal disease: The chronic hypoxia hypothesis. Kidney Int 1998;53:S74-8.
31. Dounousi E, Papavasiliou E, Makedou A, Ioannou K, Katopodis KP, Tselepis A, et al. Oxidative stress is progressively enhanced with advancing stages of CKD. Am J Kidney Dis 2006;48:752-60.
32. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev 1979;59:527-605.
33. Haase VH. Mechanisms of hypoxia responses in renal tissue. J Am Soc Nephrol 2013;24:537-41.
34. Ow CP, Ngo JP, Ullah MM, Barsha G, Meex RC, Watt MJ, et al. Absence of renal hypoxia in the subacute phase of severe renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 2018;315:F1358-69. 35. Marcussen N. Atubular glomeruli in renal artery stenosis. Lab Invest 1991;65:558-65.
36. Fries JW, Sandstrom DJ, Meyer TW, Rennke HG. Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat. Lab Invest 1989;60:205-18.
37. Kong T, Eltzschig HK, Karhausen J, Colgan SP, Shelley CS. Leucocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of b2 integrin gene expression. Proc Nat Acad Sci USA 2004;101:10440-5.
38. Postlethwaite AE, Shigemitsu H, Kanangat S. Cellular origins of fibroblasts: Possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol 2004;16:733-8.
39. Hofer T, Wenger R, Gassmann M. Oxygen sensing, HIF-1alpha stabilization and potential therapeutic strategies. Eur J Physiol 2002;443:503-7.
40. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 2010;40:294-309.
|