Nephroprotective effect of remote ischemic conditioning on type 2 diabetic rats

Document Type : Original Article

Authors

1 Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

2 Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

Abstract

Objective(s): Diabetic nephropathy is one of the main causes of kidney failure in the end stage of diabetes worldwide. The present study was conducted with the aim of using the remote ischemic conditioning (RIC) method to prevent diabetic nephropathy.
Materials and Methods: Diabetes was induced by high-fat diet (60%) and streptozotocin injection (35 mg/kg) in rats. RIC was performed by tightening a tourniquet around the upper thigh and releasing it for three cycles of 5 min of ischemia and 5 min of reperfusion daily for an 8-week duration. At the end of the experiment, serum and urine parameters were examined. Anti-oxidant enzymes and lipid peroxidation levels in the kidney were also determined along with histological examination. The expression levels of tumor necrosis factor-alpha and transforming growth factor beta genes were also evaluated. 
Results: Glucose, cholesterol, triglyceride, and HbA1c concentrations were not significantly reduced in the RIC group. On the other hand, serum creatinine, urea, and albumin levels decreased and increased in urine. Anti-oxidant enzymes did improve in the kidney significantly and the expression of tumor necrosis factor-alpha and transforming growth factor beta genes decreased significantly. Histopathological examination also showed that necrosis, epithelial damage, and leukocyte infiltration increased in the diabetic group and improved in the treatment group. 
Conclusion: The results of biochemical analysis, and enzymatic and histological examinations showed that although RIC could not reduce blood glucose and lipids, nevertheless it may delay the progression of diabetic nephropathy due to the presence of anti-inflammatory and anti-oxidant activities.

Keywords

Main Subjects


1. Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF diabetes atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 2022; 183:109119. 
2. Magliano DJ, Chen L, Carstensen B, Gregg EW, Pavkov ME, Salim A, et al. Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: A multicountry analysis of aggregate data. Lancet Diabetes Endocrinol 2022; 10:112–119. 
3. Matoori S. Diabetes and its complications. ACS pharmacology & translational science. ACS Publications; 2022; 5:513–515. 
4. Gross JL, De Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, and Zelmanovitz T. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care 2005; 28:164–176. 
5. Mansour AE, Abdelmoniem RO, Elbadawy AM, and Ibrahim WM. The utility of estimation of glomerular filtration rate by serum cystatin C as a predictor of diabetic kidney disease in both type I and type II diabetic patients: A single center study. Egypt J Intern Med 2023; 35:35-64. 
6. Ma RCW. Genetics of cardiovascular and renal complications in diabetes. J Diabetes Investig 2016; 7:139–154. 
7. Belur Nagaraj S, Pena MJ, Ju W, Heerspink HL, and Consortium Bea. Machine‐learning–based early prediction of end‐stage renal disease in patients with diabetic kidney disease using clinical trials data. Diabetes, Obes Metab 2020; 22:2479–2486. 
8. Hu Q, Chen Y, Deng X, Li Y, Ma X, Zeng J, et al. Diabetic nephropathy: Focusing on pathological signals, clinical treatment, and dietary regulation. Biomed Pharmacother 2023; 159:1-16. 
9. Koç A, Ergene N, Baltaci AK, Moğulkoç R. Effect of 3’-4’-dihydroxyflavonol on lipid per oxidation inexperimental renal ischemia-reperfusion in rats. 2019; 6: 2579-2584. 
10. Yilmaz M, Mogulkoc R, and Baltaci AK. Effect of three-week zinc and melatonin supplementation on the oxidant-anti-oxidant system in experimental renal ischemia-reperfusion in rats. Acta Clin Croat 2015; 54:395–401. 
11. Chen G, Thakkar M, Robinson C, and Doré S. Limb remote ischemic conditioning: Mechanisms, anesthetics, and the potential for expanding therapeutic options. Front Neurol 2018; 9:40-58. 
12. Heusch G, Bøtker HE, Przyklenk K, Redington A, and Yellon D. Remote ischemic conditioning. J Am Coll Cardiol 2015; 65:177–195. 
13. Yang J, Shakil F, and Cho S. Peripheral mechanisms of remote ischemic conditioning. Cond Med 2019; 2:61-68. 
14. Zhou D, Ding J, Ya J, Pan L, Wang Y, Ji X, et al. Remote ischemic conditioning: A promising therapeutic intervention for multi-organ protection. Aging (Albany NY) 2018; 10: 1825–1855. 
15. Dewitte K, Claeys M, Van Craenenbroeck E, Monsieurs K, Heidbuchel H, Hoymans V, et al. Role of oxidative stress, angiogenesis and chemo-attractant cytokines in the pathogenesis of ischaemic protection induced by remote ischaemic conditioning: Study of a human model of ischaemia-reperfusion induced vascular injury. Pathophysiology 2019; 26:53–59. 
16. Oliveira R de CS de, Brito MVH, Ribeiro RFG, Oliveira LOD, Monteiro AM, Brandão FMV, et al. Influence of remote ischemic conditioning and tramadol hydrochloride on oxidative stress in kidney ischemia/reperfusion injury in rats1. Acta Cir Bras 2017; 32:229–235. 
17. da Silva Costa FL, Teixeira RKC, Yamaki VN, Valente AL, Silva AMF, Brito MVH, et al. Remote ischemic conditioning temporarily improves anti-oxidant defense. J Surg Res 2016; 200:105–109. 
18. Pearce L, Davidson SM, and Yellon DM. Does remote ischaemic conditioning reduce inflammation? A focus on innate immunity and cytokine response. Basic Res Cardiol 2021; 116:1–20. 
19. Mollet I, Marto JP, Mendonça M, Baptista MV, and Vieira HLA. Remote but not distant: A review on experimental models and clinical trials in remote ischemic conditioning as potential therapy in ischemic stroke. Mol Neurobiol 2022; 59: 294–325. 
20. Wang L, Wang H, and Lan H. TGF-β signaling in diabetic nephropathy: An update. Diabet Nephrop 2022; 2:7–16. 
21. Abdul‐Ghani S, Fleishman AN, Khaliulin I, Meloni M, Angelini GD, and Suleiman M. Remote ischemic preconditioning triggers changes in autonomic nervous system activity: Implications for cardioprotection. Physiol Rep 2017; 5:1-13. 
22. Zhang X, Jizhang Y, Xu X, Kwiecien TD, Li N, Zhang Y, et al. Protective effects of remote ischemic conditioning against ischemia/reperfusion-induced retinal injury in rats. Vis Neurosci 2014; 31:245–252. 
23. Zhang M, Lv X-Y, Li J, Xu Z-G, and Chen L. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Exp Diabetes Res 2008; 2008:1-9. 
24. Sagoo MK and Gnudi L. Diabetic nephropathy: An overview. Diabet Nephrop Methods Protoc 2020; 3–7. 
25. Soria B, Skoudy A, and Martin F. From stem cells to beta cells: New strategies in cell therapy of diabetes mellitus. Diabetologia 2001; 44:407–415. 
26. Podkowińska A and Formanowicz D. Chronic kidney disease as oxidative stress-and inflammatory-mediated cardiovascular disease. Antioxidants 2020; 9:752-806. 
27. Charlton A, Garzarella J, Jandeleit-Dahm KAM, and Jha JC. Oxidative stress and inflammation in renal and cardiovascular complications of diabetes. Biology (Basel) 2020; 10:18-36. 
28. Rahmani AH, Alsahli MA, Khan AA, and Almatroodi SA. Quercetin, a plant flavonol attenuates diabetic complications, renal tissue damage, renal oxidative stress and inflammation in streptozotocin-induced diabetic rats. Metabolites 2023; 13:130-146. 
29. Hess DC, Blauenfeldt RA, and Andersen G. Remote ischemic conditioning: Feasible and potentially beneficial for ischemic stroke. JAMA 2022; 328:622–624. 
30. Li S, Xing X, Wang L, Xu J, Ren C, Li Y, et al. Remote ischemic conditioning reduces adverse events in patients with acute ischemic stroke complicating acute myocardial infarction: A randomized controlled trial. Crit Care 2024; 28:5-14. 
31. Heusch G. Remote ischemic conditioning: The enigmatic transfer of protection. Cardiovasc Res 2017;113:1-2.
32. Ren C, Wu H, Li D, Yang Y, Gao Y, Jizhang Y, et al. Remote ischemic conditioning protects diabetic retinopathy in streptozotocin-induced diabetic rats via anti-inflammation and anti-oxidation. Aging Dis 2018; 9:1122. 
33. Kong Y, Rogers MR, and Qin X. Effective neuroprotection by ischemic postconditioning is associated with a decreased expression of RGMa and inflammation mediators in ischemic rats. Neurochem Res 2013; 38:815–825. 
34. Monteiro AM, Couteiro RP, Silva DF da, Trindade Júnior SC, Silva RC, Sousa LFF de, et al. Remote ischemic conditioning improves rat brain anti-oxidant defense in a time-dependent mechanism. Acta Cirúrgica Bras 2021; 7: 36-43. 
35. Wu H, Xu F, Huang X, Li X, Yu P, Zhang L, et al. Lupenone improves type 2 diabetic nephropathy by regulating NF-κB pathway-mediated inflammation and TGF-β1/Smad/CTGF-associated fibrosis. Phytomedicine 2023; 118:154959. 
36. Kadhim SH, Khakzad MR, and Eshaghi A. Evaluation of the relationship between Tgf-Β expression and clinical symptoms in patients with diabetic nephropathy. J Pharm Negat Results 2023; 14:211–226. 
37. Helgeland E, Breivik LE, Vaudel M, Svendsen ØS, Garberg H, Nordrehaug JE, et al. Exploring the human plasma proteome for humoral mediators of remote ischemic preconditioning-a word of caution. PLoS One 2014; 9:1-9. 
38. Gao L, Li P, Zhang J, Hagiwara M, Shen B, Bledsoe G, et al. Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells. J Am Heart Assoc 2014; 3:e001194. 
39. Hibert P, Prunier-Mirebeau D, Beseme O, Chwastyniak M, Tamareille S, Lamon D, et al. Apolipoprotein aI is a potential mediator of remote ischemic preconditioning. PLoS One 2013; 8:1-9. 
40. Aimo A, Borrelli C, Giannoni A, Pastormerlo LE, Barison A, Mirizzi G, et al. Cardioprotection by remote ischemic conditioning: Mechanisms and clinical evidences. World J Cardiol 2015; 7:621- 632. 
41. Morley WN, Coates AM, and Burr JF. Cardiac autonomic recovery following traditional and augmented remote ischemic preconditioning. Eur J Appl Physiol 2021; 121:265–277.