Alteration of oxidative stress and inflammatory cytokines induces apoptosis in diabetic nephropathy

Sha,Jibin; Sui,Bo; Su,Xiaoqing; Meng,Qingfang; Zhang,Chenggang

doi:10.3892/mmr.2017.7522

Alteration of oxidative stress and inflammatory cytokines induces apoptosis in diabetic nephropathy

Authors:
- Jibin Sha
- Bo Sui
- Xiaoqing Su
- Qingfang Meng
- Chenggang Zhang
View Affiliations

Affiliations: School of Sports Science and Health, Shandong Sports University, Jinan, Shandong 250102, P.R. China, Department of Endoscopy, Zhangqiu People's Hospital, Jinan, Shandong 250200, P.R. China, School of Social Sports Science, Shandong Sports University, Jinan, Shandong 250102, P.R. China, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
Published online on: September 19, 2017 https://doi.org/10.3892/mmr.2017.7522
Pages: 7715-7723

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Diabetic nephropathy (DN) is one of the most significant long‑term complications in terms of morbidity and mortality for diabetic patients; however, the exact cause remains unknown. To address this, the DN model was established, and oxidative stress indexes, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH‑Px), and inflammatory cytokines, includinginterleukin‑6 (IL‑6), tumor necrosis factor‑alpha (TNF‑α) and transforming growth factor‑beta (TGF‑β), were examined by ELISA. Renal pathological alterations and cell apoptosis was examined by hematoxylin and eosin and terminal deoxynucleotidyl transferase mediated dUTP nick‑end labeling staining, respectively. The expression levels of B‑cell lymphoma‑2 (Bcl‑2), Bcl‑2 associated X (Bax) and caspase‑3 wereexamined by immunohistochemistry and western blotting. The DN model was correctly established, with lower body weight and the higher blood glucose in the diabetes model group. The expression levels of SOD and GSH‑Px were significantly decreased in the diabetes model group; however, MDA, IL‑6, TNF‑α and TGF‑β were significantly increased. The kidney was severely damaged in the diabetes model group, with inflammatory cell invasion, increasing amount of interstitial matrix and hypertrophy with vacuolar degeneration of renal tubular cells. Cell apoptosis levels were significantly increased, and Bcl‑2 was significantly decreased in the diabetes model group in contrast with that of the sham group; however, Bax and caspase‑3 were significantly increased. It suggested that increased oxidative stress and inflammatory cytokines may enhance the apoptosis levels in DN, and may provide a significant diagnostic reference for DN in diabetes patients.

View Figures

View References

1	Zhang Y, Liu T, Chen Y, Dong Z, Zhang J, Sun Y, Jin B, Gao F, Guo S and Zhuang R: CD226 reduces endothelial cell glucose uptake under hyperglycemic conditions with inflammation in type 2 diabetes mellitus. Oncotarget. 7:12010–12023. 2016. View Article : Google Scholar : PubMed/NCBI
2	Song SO, Song YD, Nam JY, Park KH, Yoon JH, Son KM, Ko Y and Lim DH: Epidemiology of type 1 diabetes mellitus in Korea through an investigation of the national registration project of type 1 diabetes for the reimbursement of glucometer strips with additional analyses using claims data. Diabetes Metab J. 40:35–45. 2016. View Article : Google Scholar : PubMed/NCBI
3	Bhatt AB, Mulvey CK, Qasim AN, Nair JV, Rickels MR, Prenner SB, Iqbal N and Reilly MP: Selective association of electrocardiographic abnormalities with insulin sensitivity and beta-cell function in type 2 diabetes mellitus: A cross sectional analysis. Diabetes Metab Res Rev. 32:736–744. 2016. View Article : Google Scholar : PubMed/NCBI
4	Zhou J, Du X, Long M, Zhang Z, Zhou S and Qian G: Neuroprotective effect of berberine is mediated by MAPK signaling pathway in experimental diabetic neuropathy in rats. Eur J Pharmacol. 774:87–94. 2016. View Article : Google Scholar : PubMed/NCBI
5	Tesfaye S, Selvarajah D, Gandhi R, Greig M, Shillo P, Fang F and Wilkinson ID: Diabetic peripheral neuropathy may not be as its name suggests: Evidence from magnetic resonance imaging. Pain. 157 Suppl 1:S72–S80. 2016. View Article : Google Scholar : PubMed/NCBI
6	Erbaş O, Oltulu F, Yilmaz M, Yavaşoğlu A and Taşkıran D: Neuroprotective effects of chronic administration of levetiracetam in a rat model of diabetic neuropathy. Diabetes Res Clin Pract. 114:106–116. 2016. View Article : Google Scholar : PubMed/NCBI
7	Motawi TK, Darwish HA, Hamed MA, El-Rigal NS and Naser AFA: A therapeutic insight of niacin and coenzyme Q10 against diabetic encephalopathy in rats. Mol Neurobiol. 54:1601–1611. 2017. View Article : Google Scholar : PubMed/NCBI
8	Cai XJ, Xu HQ and Lu Y: C-peptide and diabetic encephalopathy. Chin Med Sci J. 26:119–125. 2011. View Article : Google Scholar : PubMed/NCBI
9	Wang YY, Zhang D, Jiang ZY, Lu XQ, Zheng X, Yu YJ, Wang YG and Dong J: Positive association between betatrophin and diabetic retinopathy risk in type 2 diabetes patients. Horm Metab Res. 48:169–173. 2016. View Article : Google Scholar : PubMed/NCBI
10	Micheletti JM, Hendrick AM, Khan FN, Ziemer DC and Pasquel FJ: Current and next generation portable screening devices for diabetic retinopathy. J Diabetes Sci Technol. 10:295–300. 2016. View Article : Google Scholar : PubMed/NCBI
11	Ebrahimi MH and Gharibi H: A case study of a patient with diabetic retinopathy. Diabetes Metab Syndr. 10:166–168. 2016. View Article : Google Scholar : PubMed/NCBI
12	Zheng Z and Zheng F: Immune cells and inflammation in diabetic nephropathy. J Diabetes Res. 2016:18416902016. View Article : Google Scholar : PubMed/NCBI
13	Skov J, Christiansen JS and Poulsen PL: Hypertension and diabetic nephropathy. Endocr Dev. 31:97–107. 2016. View Article : Google Scholar : PubMed/NCBI
14	Lytvyn Y, Bjornstad P, Pun N and Cherney DZ: New and old agents in the management of diabetic nephropathy. Curr Opin Nephrol Hypertens. 25:232–239. 2016. View Article : Google Scholar : PubMed/NCBI
15	Zheng S, Powell DW, Zheng F, Kantharidis P and Gnudi L: Diabetic nephropathy: Proteinuria, inflammation, and fibrosis. J Diabetes Res. 2016:52415492016. View Article : Google Scholar : PubMed/NCBI
16	Wanchoo R and Jhaveri KD: Nephrology crosswords: Diabetic nephropathy. Kidney Int. 88:647–648. 2015. View Article : Google Scholar : PubMed/NCBI
17	Chan GC and Tang SC: Diabetic nephropathy: Landmark clinical trials and tribulations. Nephrol Dial Transplant. 31:359–368. 2016. View Article : Google Scholar : PubMed/NCBI
18	Zhang Y, Yang J, Zheng M, Wang Y, Ren H, Xu Y, Yang Y, Cheng J, Han F, Yang X, et al: Clinical characteristics and predictive factors of subclinical diabetic nephropathy. Exp Clin Endocrinol Diabetes. 123:132–138. 2015. View Article : Google Scholar : PubMed/NCBI
19	Barchetta I, Guglielmi C, Bertoccini L, Calella D, Manfrini S, Secchi C, Pozzilli P and Cavallo MG: IMDIAB group: Therapy with proton pump inhibitors in patients with type 2 diabetes is independently associated with improved glycometabolic control. Acta Diabetol. 52:873–880. 2015. View Article : Google Scholar : PubMed/NCBI
20	Bhat KG and Periasamy PK: Effect of long-term transfusion therapy on the glycometabolic status and pancreatic Beta cell function in patients with Beta thalassemia major. J Family Med Prim Care. 3:119–123. 2014. View Article : Google Scholar : PubMed/NCBI
21	Chen B, Niu YW, Xie T, Miao MY, Tian M, Ji XY, Qing C and Lu SL: Relationship between cutaneous glycometabolic disorders and cutaneous neuropathy in diabetic rats. Zhonghua Shao Shang Za Zhi. 27:139–144. 2011.(In Chinese). PubMed/NCBI
22	Tian ML, Shen Y, Sun ZL and Zha Y: Efficacy and safety of combining pentoxifylline with angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in diabetic nephropathy: A meta-analysis. Int Urol Nephrol. 47:815–822. 2015. View Article : Google Scholar : PubMed/NCBI
23	Patil MR, Mishra A, Jain N, Gutch M and Tewari R: Weight loss for reduction of proteinuria in diabetic nephropathy: Comparison with angiotensin-converting enzyme inhibitor therapy. Indian J Nephrol. 23:108–113. 2013. View Article : Google Scholar : PubMed/NCBI
24	Abu-Romeh SH, Nawaz MK, Ali JH, Al-Suhaili AR and Abu-Jayyab AK: Short-term effect of angiotensin-converting enzyme inhibitor enalapril in incipient diabetic nephropathy. Clin Nephrol. 31:18–21. 1989.PubMed/NCBI
25	Vavra JJ, Deboer C, Dietz A, Hanka LJ and Sokolski WT: Streptozotocin, a new antibacterial antibiotic. Antibiot Annu. 7:230–235. 1959.PubMed/NCBI
26	Zhu D, Zhang L, Cheng L, Ren L, Tang J and Sun D: Pancreatic kininogenase ameliorates renal fibrosis in streptozotocin induced-diabetic nephropathy rat. Kidney Blood Press Res. 41:9–17. 2016. View Article : Google Scholar : PubMed/NCBI
27	Zhang Y, Hu T, Zhou H, Jin G and Yang Y: Antidiabetic effect of polysaccharides from Pleurotus ostreatus in streptozotocin-induced diabetic rats. Int J Biol Macromol. 83:126–132. 2016. View Article : Google Scholar : PubMed/NCBI
28	Yeh PT, Huang HW, Yang CM, Yang WS and Yang CH: Astaxanthin inhibits expression of retinal oxidative stress and inflammatory mediators in streptozotocin-induced diabetic rats. PLoS One. 11:e01464382016. View Article : Google Scholar : PubMed/NCBI
29	Lindblom R, Higgins G, Coughlan M and de Haan JB: Targeting mitochondria and reactive oxygen species-driven pathogenesis in diabetic nephropathy. Rev Diabet Stud. 12:134–156. 2015. View Article : Google Scholar : PubMed/NCBI
30	Nishikawa T, Brownlee M and Araki E: Mitochondrial reactive oxygen species in the pathogenesis of early diabetic nephropathy. J Diabetes Investig. 6:137–139. 2015. View Article : Google Scholar : PubMed/NCBI
31	Ha H, Hwang IA, Park JH and Lee HB: Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract. 82 Suppl 1:S42–S45. 2008. View Article : Google Scholar : PubMed/NCBI
32	Utsumi K, Yasuda F, Watanabe Y, Higo S, Hirama A, Fujita E, Ueda K, Mii A, Kaneko T, Mishina M, et al: Effects of olmesartan and imidapril on the plasma adiponectin, P-selectin, and MDA-LDL levels of diabetic nephropathy patients. Clin Chim Acta. 413:348–349. 2012. View Article : Google Scholar : PubMed/NCBI
33	Rakitianskaia IA, Riabov SI, Dubrova AG, Azanchevskaia SV, Riabova TS and Gurkov AS: The role of IL-6 in the development of morphological changes in renal tissue in elderly patients with type 2 diabetes complicated by diabetic nephropathy. Adv Gerontol. 25:632–637. 2012.(In Russian). PubMed/NCBI
34	Svensson MK and Eriksson JW: Change in the amount of body fat and IL-6 levels is related to altered insulin sensitivity in type 1 diabetes patients with or without diabetic nephropathy. Horm Metab Res. 43:209–215. 2011. View Article : Google Scholar : PubMed/NCBI
35	Guclu A, Erken HA, Erken G, Dodurga Y, Yay A, Özçoban Ö, Şimşek H, Akçılar A and Koçak FE: The effects of ozone therapy on caspase pathways, TNF-α, and HIF-1α in diabetic nephropathy. Int Urol Nephrol. 48:441–450. 2016. View Article : Google Scholar : PubMed/NCBI
36	Navarro JF and Mora-Fernández C: The role of TNF-alpha in diabetic nephropathy: Pathogenic and therapeutic implications. Cytokine Growth Factor Rev. 17:441–450. 2006. View Article : Google Scholar : PubMed/NCBI
37	Elsherbiny NM, Al-Gayyar MM and Abd El Galil KH: Nephroprotective role of dipyridamole in diabetic nephropathy: Effect on inflammation and apoptosis. Life Sci. 143:8–17. 2015. View Article : Google Scholar : PubMed/NCBI
38	Susztak K, Raff AC, Schiffer M and Böttinger EP: Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 55:225–233. 2006. View Article : Google Scholar : PubMed/NCBI
39	Ghule AE, Jadhav SS and Bodhankar SL: Trigonelline ameliorates diabetic hypertensive nephropathy by suppression of oxidative stress in kidney and reduction in renal cell apoptosis and fibrosis in streptozotocin induced neonatal diabetic (nSTZ) rats. Int Immunopharmacol. 14:740–748. 2012. View Article : Google Scholar : PubMed/NCBI
40	Baba K, Minatoguchi S, Sano H, Kagawa T, Murata I, Takemura G, Hirano T, Ohashi H, Takemura M, Fujiwara T and Fujiwara H: Involvement of apoptosis in patients with diabetic nephropathy: A study on plasma soluble Fas levels and pathological findings. Nephrology (Carlton). 9:94–99. 2004. View Article : Google Scholar : PubMed/NCBI
41	Borkan SC: The role of BCL-2 family members in acute kidney injury. Semin Nephrol. 36:237–250. 2016. View Article : Google Scholar : PubMed/NCBI
42	Kuribayashi K, Mayes PA and El-Deiry WS: What are caspases 3 and 7 doing upstream of the mitochondria? Cancer Biol Ther. 5:763–765. 2006. View Article : Google Scholar : PubMed/NCBI
43	Lakhani SA, Masud A, Kuida K, Porter GA Jr, Booth CJ, Mehal WZ, Inayat I and Flavell RA: Caspases 3 and 7: Key mediators of mitochondrial events of apoptosis. Science. 311:847–851. 2006. View Article : Google Scholar : PubMed/NCBI