Saxagliptin Attenuates Diabetic Nephropathy with Suppressing Oxidative Stress by Inhibiting AGEs-RAGE Axis in Streptozotocin-Induced Diabetic Rats
American Journal of Internal Medicine
Volume 6, Issue 6, November 2018, Pages: 161-169
Received: Sep. 16, 2018;
Accepted: Oct. 11, 2018;
Published: Nov. 5, 2018
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Ye Feng, Department of Endocrinology and Metabolism Disease, the First Affiliated Hospital, Zhejiang University, Hangzhou, China
Chengjiang Li, Department of Endocrinology and Metabolism Disease, the First Affiliated Hospital, Zhejiang University, Hangzhou, China
Yuehuan Liu, Zhejiang Center of Laboratory Animals, Zhangjiang Academy of Medical Sciences, Hangzhou, China
Long Zhang, Department of Endocrinology, Ningbo Medical Treatment Center Lihuili Hospital, Ningbo, China
Zhe Zhang, Department of Endocrinology and Metabolism Disease, the First Affiliated Hospital, Zhejiang University, Hangzhou, China
As a dipeptidyl peptidase-4 (DPP-4) inhibitor used in diabetes mellitus (DM) therapy, saxagliptin (Saxa) has been reported an additional protective benefit of diabetic nephropathy (DN), which might be independent of its glucose-lowering effect. However, the mechanism is not fully understood. In this study, STZ-induced DM rat model received a placebo or Saxa (10mg or 20mg/kg, 8-10 rats in each group). Blood glucose, serum lipid, creatinine, blood urea nitrogen, as well as urine protein and albumin concentration, were examined. Gene expression and protein level of advanced glycation end products (AGEs) and their receptor (RAGE) were also tested. Moreover, markers for oxidative stress and antioxidant ability were determined. The results showed moderate albuminuria in diabetic rats was attenuated after Saxa treatment, consistent with morphological improvement supported by histological analysis. Both AGEs and RAGE levels were elevated in DM group but reduced after Saxa administration. Furthermore, the level of malondialdehyde (MAD), Caspase 3, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in kidney were much lower in Saxa group compared with DM group, indicating the oxidation and apoptosis in DM were ameliorated by Saxa. On the other hand, markers of antioxidation such as total antioxidation capability (TAOC), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD), had a relevant increase, suggesting enhanced antioxidation in the kidney. In conclusion, these findings show that Saxa possesses anti-oxidative activity to ameliorate diabetic renal damage, which is related to the regulation of the AGEs-RAGE axis.
Saxagliptin Attenuates Diabetic Nephropathy with Suppressing Oxidative Stress by Inhibiting AGEs-RAGE Axis in Streptozotocin-Induced Diabetic Rats, American Journal of Internal Medicine.
Vol. 6, No. 6,
2018, pp. 161-169.
A. T. Reutens, R. C. Atkins, Epidemiology of Diabetic Nephropathy, Diabetes and the Kidney, Lai KN, Tang SCW ed., Karger Publishers, Switzerland, 2011.
T. Zelmanovitz, F. Gerchman, A. P. Balthazar, et al, Diabetic nephropathy, Diabetol. Metab. Syndr. 1 (2009) 10.
E. Ritz, Diabetic nephropathy, Saudi Journal of Kidney Disease and Transplantation. 17 (2006) 481-490.
P. Fioretto, M. Mauer, Histopathology of diabetic nephropathy, Semin, Nephrol. 27 (2007) 195-207.
M. K. Arora, U. K. Singh, Oxidative stress: meeting multiple targets in pathogenesis of diabetic nephropathy, Curr. Drug. Targets. 15 (2014) 531-538.
S. Y. Goh, M. E. Cooper, Clinical review: the role of advanced glycation end products in progression and complications of diabetes, J. Clin. Endocrinol. Metab. 93 (2008) 1143-1152.
S. C. Tang, L. Y. Chan, J. C. Leung, et al, Differential effects of advanced glycation end-products on renal tubular cell inflammation, Nephrology (Carlton). 16 (2011) 417-425.
A. G. Miranda-Díaz, L. Pazarín-Villaseñor, F. G. Yanowsky-Escatell, J. Andrade-Sierra, Oxidative Stress in Diabetic Nephropathy with Early Chronic Kidney Disease, J. Diabetes. Res. 2016 (2016) 7047238.
O. Mosenzon, G. Leibowitz, D. L. Bhatt, et al, Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial, Diabetes. Care. 40 (2017) 69-76.
E. Civantos, E. Bosch, E. Ramirez, et al, Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway, Diabetes. Metab. Syndr. Obes. 7 (2017) 207-222.
A. kh. Lim, Diabetic nephropathy-complications and treatment, Int. J. Nephrol. Renovasc. Dis. 15 (2014) 361-381.
M. C. Iglesias-De La Cruz, P. Ruiz-Torres, J. Alcamí J, et al, Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells, Kidney. Int. 59 (2001) 87-95.
N. Kashihara, Y. Haruna, V. K. Kondeti, Y. S. Kanwar, Oxidative stress in diabetic nephropathy, Curr. Med. Chem. 17 (2010) 4256-4269.
V. Jakus, N. Rietbrock, Advanced glycation end-products and the progress of diabetic vascular complications. Physiol. Res. 53 (2004) 131-142.
J. S. Huang, J. Y. Guh, H. C. Chen, et al, Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells, J. Cell. Biochem. 81 (2001) 102-113.
Y. M. Li, T. Mitsuhashi, D. Wojciechowicz, et al, Molecular identity and cellular distribution of advanced glycation endproduct receptors: relationship of p60 to OST-48 and p90 to 80K-H membrane proteins, Proc. Natl. Acad. Sci. USA. 93 (1996) 11047-11052.
S. Yamagishi, T. Matsui, Advanced glycation end products, oxidative stress and diabetic nephropathy. Oxid. Med. Cell. Longev. 3 (2010) 101-108.
V. P. Singh, A. Bali, N. Singh, A. S. Jaggi, Advanced glycation end products and diabetic complications, Korean. J. Physiol. Pharmacol. 18 (2014) 1-14.
E. Stitt-Cavanagh, L. MacLeod, C. Kennedy, The podocyte in diabetic kidney disease, ScientificWorldJournal. 14 (2009) 1127-1139.
G. H. Tesch, A. K. Lim, Recent insights into diabetic renal injury from the db/db mouse model of type 2 diabetic nephropathy, Am. J. Physiol. Renal. Physiol. 300 (2011) F301-310.
L. Ferreira, E. Teixeira-de-Lemos, F. Pinto, et al, Effects of Sitagliptin Treatment on Dysmetabolism, Inflammation, and Oxidative Stress in an Animal Model of Type 2 Diabetes (ZDF Rat), Mediators. Inflamm. 2010 (2010) 592760.
W. J. Wang, C. H. Chang, M. F. Sun, et al, DPP-4 inhibitor attenuates toxic effects of indoxyl sulfate on kidney tubular cells, PLoS. One. 22 (2014) e93447.
K. Kanasaki, S. Shi, M. Kanasaki, et al, Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen, Diabetes. 63 (2014) 2120-2131.
R. Kodera, K. Shikata, T. Takatsuka, et al, Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes, Biochem. Biophys. Res. Commun. 443 (2014) 828-833.
Y. Ishibashi, T. Matsui, S. Maeda, et al, Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor, Cardiovasc. Diabetol. 12 (2013) 125.
T. Matsui, S. Nakashima, Y. Nishino, et al, Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis, Lab. Invest. 95 (2015) 525-533.
S. Nakashima, T. Matsui, M. Takeuchi, S. I. Yamagishi, Linagliptin blocks renal damage in type 1 diabetic rats by suppressing advanced glycation end products-receptor axis, Horm. Metab. Res. 46 (2014) 717-721.
M. Gangadharan Komala, S. Gross, A. Zaky, et al, Saxagliptin reduces renal tubulointerstitial inflammation, hypertrophy and fibrosis in diabetes, Nephrology (Carlton). 21 (2016) 423-431.
Y. Birnbaum, M. Bajaj, J. Qian, Y. Ye, Dipeptidyl peptidase-4 inhibition by Saxagliptin prevents inflammation and renal injury by targeting the Nlrp3/ASC inflammasome, BMJ. Open. Diabetes. Res. Care. 4 (2016) e000227.