• Ismaeel Bin-Jaliah Department of Physiology, College of Medicine, King Khalid University, PO Box 641, Abha, 61421, Aseer, Saudi Arabia
Keywords: Chronic unpredictable stress, Oxidative stress, Apoptosis, Na /K -ATPase


Background: Recently, some shocking epidemics of chronic kidney disease of undetermined origin have been reported. In this regard, numerous lines of evidence suggest that socioeconomic and environmental stressors have a key role, an effect that needs further confirmation. The present study was undertaken to explore the effect of Chronic Unpredictable Stress (CUS) on kidney function and structure in rats. Methods: It was a randomized control trial. Rats were divided into control and experimental groups (n=8 each). The experimental group (CUS group) consisted of rats which were exposed to a set of mild stressors for 21 days. After that, biochemical and molecular studies were conducted to measure kidney function tests, renal oxidative stress, inflammatory response, components of intrinsic apoptosis, as well as function of Na+/K+-ATPase. In addition, renal histopathological study was conducted. Results: Chronic Unpredictable Stress resulted in sever renal damage as indicated by enhanced serum urea and reduced creatinine clearance (Ccr), also evident by the severe glomerular and tubular damage and neutrophils infiltration. Concomitantly, CUS exaggerated oxidative stress and lipid peroxidation by inhibiting activities of endogenous antioxidant enzymes and activating renal inflammatory response. CUS stress resulted in inhibiting activities of renal Na+/K+-ATPase and induced Na+ retention. CUS activated intrinsic apoptotic pathway as evident by decrease renal levels of Bcl-2 and enhanced levels of caspase 3 and mRNA levels of p53 and Bax. Conclusion: Chronic Unpredictable Stress causes renal damage by exaggerating oxidative stress, inhibiting Na+/K+-ATPase pump activity and activation of inflammation and apoptosis.

Pak J Physiol 2016;12(3):3–8


1. Samarghandian S, Azimi-Nezhad M, Samini F. Preventive effect of safranal against oxidative damage in aged male rat brain. Exp Anim 2015;64:65–71.
2. Mantle D, Preedy VR. Free radicals as mediators of alcohol toxicity. Adverse Drug React Toxicol 1999;18:235–52.
3. Kamper EF, Chatzigeorgiou A, Tsimpoukidi O, Kamper M, Dalla C, Pitychoutis PM, et al. Sex differences in oxidant/ antioxidant balance under a chronic mild stress regime. Physiol Behav 2009;98:215–22.
4. Halliwell B. Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? The Lancet 1994;344(7):721–4.
5. Fontella FU, Siqueira RI, Vasconcellos APS. Repeated restraint stress induces oxidative damage in rat hippocampus. Neurochem Res 2005;30:105–11.
6. Brydon L, Magid K, Steptoe A: Platelets, coronary heart disease, and stress. Brain Behav Immun 2006;20(2):113–9.
7. Joëls M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci 2009;10:459–66.
8. Rodrigo R, Rivera G. Renal damage mediated by oxidative stress: a hypothesis of protective effects of red wine. Free Radic Biol Med 2002;33:409–22.
9. Shah SV, Walker PD. Evidence suggesting a role for hydroxyl radical in glycerol-induced acute renal failure. Am J Physiol 1988;255:F438–F443.
10. Klahr S. Urinary tract obstruction. Semin Nephrol 2001;21:133–45.
11. Kitamura M, IshikawaY. Oxidant-induced apoptosis of glomerular cells: intracellular signaling and its intervention by bioflavonoid. Kidney Int 1999;56:1223–9.
12. Handelman GJ, Walter MF, Adhikarla R, Gross J, Dallal GE, Levin NW, et al. Elevated plasma F2-isoprostanes in patients on long-term hemodialysis. Kidney Int 2001;59:1960–6.
13. Martín-Mateo MC, Sanchez-Portugal M, Iglesias S, de Paula A, Bustamante J. Oxidative stress in chronic renal failure. Ren Fail 1999;21:155–67.
14. Trabanino RG, Aguilar R, Silva CR, Mercado MO, Merino RL. End-stage renal disease among patients in a referral hospital in ElSalvador. Rev Panam Salud Pública 2002;12(3):202–6.
15. Correa-Rotter R, Wesseling C, Johnson RJ. CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy. Am J Kidney Dis 2014;63(3):506–20.
16. Brooks DR, Ramirez-Rubio O, Amador JJ. CKD in Central America: a hot issue. Am J Kidney Dis 2012;59(4),481–4.
17. Fukagawa M. Nephrology in Earthquakes: Sharing experiences and information. Clin J Am Soc Nephrol 2007;2:803–8.
18. Bruce MA, Beech BM, Sims M, Brown TN, Wyatt SB, Taylor HA, et al. Social environmental stressors, psychological factors, and kidney disease. J Investig Med 2009;57(4):583–9.
19. Norris K, Nissenson AR. Race, gender, and socioeconomic disparities in CKD in the United States. J Am Soc Nephrol 2008;19(7):1261–70.
20. National Institute of Health, 1996. Guide for the care and use of laboratory animals. Revised. DHEW Publication (NIH), Office of Science and Health Reports, DRR/NIH, Bethesda, MD. Available at
21. Li GY, Xie P, Li HY, Hao L, Xiong Q, Qiu T. Involment of p53, Bax, and Bcl-2 pathway in microcystins-induced apoptosis in rat testis. Environ Toxicol 2011;26(2):111–7.
22. Klahr S, Nephrology forum: obstructive nephropathy. Kidney Int 1998;54:286–300.
23. Scheuer H, Gwinner W, Hohbach J, Gröne EF, Brandes RP, Malle E, et al. Oxidant stress in hyperlipidemia-induced renal damage. Am J Physiol 2000;278:F63–F74.
24. Zager RA, Burkhart K. Myoglobin in proximal human kidney cells: roles of Fe, Ca2+, H2O2, a mitochondrial electron transport. Kidney Int 1997;51:728–38.
25. Rovin BH, Phan LT. Chemotactic factors and renal inflammation. Am J Kidney Dis 1998;31(6):1065–84.
26. Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. J Clin Invest 2001;107:7–11.
27. Grippo AJ, Francis J, Beltz TG, Felder RB, Johnson AK. Neuroendocrine and cytokine profile of 1206 chronic mild stress-induced anhedonia. Physiol Behav 2005;84:697–706.
28. von Känel R, Bellingrath S, Kudielka BM. Association between burnout and circulating levels of pro- and anti-inflammatory cytokines in schoolteachers. J Psychosom Res 2008;65:51–9.
29. Devarajan P. Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 2006;17:1503–20.
30. Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol 2003;14:(8):2199–210.
31. Bertorello AM, Ridge KM, Chibalin AV, Katz AI, Sznajder JI. Isoproterenol increases Na+/K+-ATPase activity by membrane insertion of alpha subunits in lung alveolar cells. Am J Physiol 1999;276:L20–L27.
32. Fujji Y, Takemoto F, Katz AI. Early effects of aldosteone on Na+/K+ pump in rat cortical collecting tubules. Am J Physiol 1990;259:F40–F45.
33. Ferretti G, Rabini R, Bacchetti T, Vignini A, Salvolini E, Ravagali F, et al. Glycated low density lipoproteins modify platelet properties: A compositional and functional study. J Clin Endocrinol Metab 2002;87:2180–4.
34. Therien AG, Blostein R. Mechanisms of sodium pump regulation. Am J Physiol 2000;279:C541–C566.
35. Ogimoto G, Yudowski GA, Barker CJ, Köhler M, Katz AI, Féraille E, et al. G protein-coupled receptors regulate Na+, K+-ATPase activity and endocytosis by modulating the recruitment of adaptor protein 2 and clathrin. Proc Natl Acad Sci USA 2000;97:3242–7.
36. Bertorello A, Hökfelt T, Goldstein M, Aperia A. Proximal tubule Na+/K+-ATPase activity is inhibited during high-salt diet (Evidence for DA-mediated effect). Am J Physiol-Ren Physiol 1988;254(6):F795–801.
37. Seri I, Kone BC, Gullans SR, Aperia A, Brenner BM, Ballermann BJ. Influence of Na intake on dopamine-induced inhibition of renal cortical Na+/K+-ATPase. Am J Physiol 1990;258(1):F52–60.


Download data is not yet available.
How to Cite