DPP-4 inhibitor sitagliptin prevents inflammation and oxidative stress of heart and kidney in two kidney and one clip (2K1C) rats

Diabetology & Metabolic Syndrome

Hasan Mahmud Reza¹  Md. Abu Taher Sagor¹  Preeti Jain¹  Mohammed Riaz Hasan Chowdhury¹  Md. Ashraful Alam¹ 

[1] Department of Pharmaceutical Sciences, School of Life Sciences, North South University, Bashundhara, Dhaka, Bangladesh

关键词: Malondialdehyde;    Oxidative stress;    Inflammation;    Fibrosis;    Sitagliptin;   

Others  :  1234348
DOI  :  10.1186/s13098-015-0095-3

 received in 2015-04-30, accepted in 2015-11-02,  发布年份 2015

【 摘 要 】

Background

Hyperglycemia and insulin resistance often develop cardiovascular and nephrological dysfunction in diabetic patients. Sitagliptin is used to treat diabetes and showed potential benefit in lowering increased blood glucose level in diabetes. This investigation reports the effect of sitagliptin treatment on oxidative stress in kidney and heart of 2K1C rats.

Methods

Male Long Evans rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2K1C) method]. These animals entered a 4-weeks dosing period with sitagliptin. Blood and urine sampling and organ harvesting were finally performed. Blood plasma, heart, kidney tissues and urine were tested for the assessment of inflammation and oxidative stress in kidney and heart of 2K1C rats after 4 weeks of surgery.

Results

2K1C rats showed cardiac hypertrophy, increased left ventricular wet weight compared to sham which was not significantly altered by sitagliptin treatment. Uric acid and creatinin concentrations were also increased in 2K1C rats. Sitagliptin significantly prevented the elevation of uric acid and creatinin concentration in plasma and urine in this rat model. Oxidative stress markers in plasma such as malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) concentrations were increased in the 2K1C rats as compared to sham-operated animals. Increased concentrations of these oxidative stress markers were also normalized by sitagliptin treatment. 2K1C rats also showed increased level of uric acid and creatinine both in plasma and urine; which are also reduced to normal level in sitagliptin treated rats. Moreover, 2K1C surgery initiated inflammatory cell infiltration, increased MPO activity and fibrosis in both heart and kidneys which were further ameliorated by sitagliptin treatment.

Conclusion

Our study suggests that sitagliptin treatment in 2K1C rats prevented inflammation and fibrosis of heart and kidney by ameliorating elevated oxidative stress in heart and kidney tissues.

【 授权许可】

   
2015 Alam et al.

【 图 表 】

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【 参考文献 】

• [1]Zitkus BS: Update on the American Diabetes Association Standards of Medical Care. Nurse Pract. 2014, 39(8):22-32.
• [2]AmericanDiabetes A: Standards of medical care in diabetes–2014 Diabetes Care. 2014, 37(Suppl 1):S14-S80.
• [3]Zhang Y, Shao L, Ma A, Guan G, Wang J, Wang Y, et al.: Telmisartan delays myocardial fibrosis in rats with hypertensive left ventricular hypertrophy by TGF-beta1/Smad signal pathway. Hypertension Res. 2014, 37(1):43-49.
• [4]López B, González A, Querejeta R, Larman M, Díez J: Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol 2006, 48(1):89-96.
• [5]Shirwany A, Weber KT: Extracellular matrix remodeling in hypertensive heart disease. J Am Coll Cardiol 2006, 48(1):97-98.
• [6]Alam MA, Sernia C, Brown L: Ferulic acid improves cardiovascular and kidney structure and function in hypertensive rats. J Cardiovasc Pharmacol 2013, 61(3):240-249.
• [7]Olsen MH, Christensen MK, Wachtell K, Tuxen C, Fossum E, Bang LE, et al.: Markers of collagen synthesis is related to blood pressure and vascular hypertrophy: a LIFE substudy. J Hum Hypertens 2005, 19(4):301-307.
• [8]Alam MA, Uddin SJ, Brown L: Mitogen-activated protein kinase and natural phenolic compounds in cardiovascular remodeling. In Studies in natural products chemistry. Edited by Atta ur R. Elsevier, Amsterdam; 2012:159-190.
• [9]Li JM, Gall NP, Grieve DJ, Chen M, Shah AM: Activation of NADPH oxidase during progression of cardiac hypertrophy to failure. Hypertension 2002, 40(4):477-484.
• [10]Seddon M, Looi YH, Shah AM: Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 2007, 93(8):903-907.
• [11]Sagor MAT, Tabassum N, Potol MA, Alam MA: Xanthine oxidase inhibitor, allopurinol, prevented oxidative stress, fibrosis, and myocardial damage in isoproterenol induced aged rats. Oxidative Med Cellular Longevity. 2015, 2015:9.
• [12]Hansen PR: Role of neutrophils in myocardial ischemia and reperfusion. Circulation 1995, 91(6):1872-1885.
• [13]Basile DP, Donohoe DL, Phillips SA, Frisbee JC: Enhanced skeletal muscle arteriolar reactivity to ANG II after recovery from ischemic acute renal failure. Am J Physiol Regul Integr Comp Physiol 2005, 289(6):R1770-R1776.
• [14]Tsutsui H, Matsushima S, Kinugawa S, Ide T, Inoue N, Ohta Y, et al.: Angiotensin II type 1 receptor blocker attenuates myocardial remodeling and preserves diastolic function in diabetic heart. Hypertension Res. 2007, 30(5):439-449.
• [15]Helle F, Hultström M, Skogstrand T, Palm F, Iversen BM: Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C. Am J Physiol Renal Physiol. 2009, 296(1):F78-F86.
• [16]Navar LG, Harrison-Bernard LM, Nishiyama A, Kobori H: Regulation of intrarenal angiotensin II in hypertension. Hypertension 2002, 39(2 Pt 2):316-322.
• [17]Garrido AM, Griendling KK: NADPH oxidases and angiotensin II receptor signaling. Mol Cell Endocrinol 2009, 302(2):148-158.
• [18]Touyz RM, Tabet F, Schiffrin EL: Redox-dependent signalling by angiotensin II and vascular remodelling in hypertension. Clin Exp Pharmacol Physiol 2003, 30(11):860-866.
• [19]Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Oshima T, Chayama K: Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med 2002, 346(25):1954-1962.
• [20]Lerman LO, Nath KA, Rodriguez-Porcel M, Krier JD, Schwartz RS, Napoli C, et al.: Increased oxidative stress in experimental renovascular hypertension. Hypertension 2001, 37(2 Pt 2):541-546.
• [21]Zhao W, Chen SS, Chen Y, Ahokas RA, Sun Y: Kidney fibrosis in hypertensive rats: role of oxidative stress. Am J Nephrol 2008, 28(4):548-554.
• [22]Rizzi E, Ceron CS, Guimaraes DA, Prado CM, Rossi MA, Gerlach RF, et al.: Temporal changes in cardiac matrix metalloproteinase activity, oxidative stress, and TGF-beta in renovascular hypertension-induced cardiac hypertrophy. Exp Mol Pathol 2013, 94(1):1-9.
• [23]Drucker DJ: Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 2007, 30(6):1335-1343.
• [24]Drucker DJ: Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterol. 2002, 122(2):531-544.
• [25]Aroor AR, Sowers JR, Bender SB, Nistala R, Garro M, Mugerfeld I, et al.: Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male zucker obese rats. J Endocrinol 2013, 154(7):2501-2513.
• [26]Nistala R, Habibi J, Aroor A, Sowers JR, Hayden MR, Meuth A, et al.: DPP4 inhibition attenuates filtration barrier injury and oxidant stress in the zucker obese rat. Obesity. 2014, 22(10):2172-2179.
• [27]Liu L, Liu J, Wong WT, Tian XY, Lau CW, Wang YX, et al.: Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension 2012, 60(3):833-841.
• [28]Marney A, Kunchakarra S, Byrne L, Brown NJ: Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension 2010, 56(4):728-733.
• [29]Vaghasiya J, Sheth N, Bhalodia Y, Manek R: Sitagliptin protects renal ischemia reperfusion induced renal damage in diabetes. Regul Pept 2011, 166(1–3):48-54.
• [30]Liu WJ, Xie SH, Liu YN, Kim W, Jin HY, Park SK, et al.: Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats. J Pharmacol Exp Ther 2012, 340(2):248-255.
• [31]Mega C, de Lemos ET, Vala H, Fernandes R, Oliveira J, Mascarenhas-Melo F, et al.: Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat). Exp Diabetes Res. 2011, 2011:162092.
• [32]Niehaus WG, Samuelsson B: Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem 1968, 6(1):126-130.
• [33]Tracey WR, Tse J, Carter G: Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors. J Pharmacol Exp Ther 1995, 272(3):1011-1015.
• [34]Witko-Sarsat V, Friedlander M, Capeillère-Blandin C, Nguyen-Khoa T, Nguyen A, Zingraff J, et al.: Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 1996, 49:1304-1313.
• [35]Tiwari BK, Kumar D, Abidi AB, Rizvi SI: Efficacy of composite extract from leaves and fruits of medicinal plants used in traditional diabetic therapy against oxidative stress in alloxan-induced diabetic rats. ISRN Pharmacol. 2014, 2014:7.
• [36]Chance B, Maehly A: Assay of catalase and peroxidases. Methods Enzymol. 1955, 11:764-775.
• [37]Khan R: Protective effects of Sonchus asper (L.) Hill, (Asteraceae) against CCl 4 -induced oxidative stress in the thyroid tissue of rats. BMC Complement Altern Med. 2012, 12(1):181. BioMed Central Full Text
• [38]Bradley PP, Priebat DA, Christensen RD, Rothstein G: Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Investigative Dermatol. 1982, 78(3):206-209.
• [39]Doggrell SA, Brown L: Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res. 1998, 39(1):89-105.
• [40]Thurston H, Bing RF, Swales JD: Reversal of two-kidney one clip renovascular hypertension in the rat. Hypertension 1980, 2(3):256-265.
• [41]Silambarasan T, Raja B: Diosmin, a bioflavonoid reverses alterations in blood pressure, nitric oxide, lipid peroxides and antioxidant status in DOCA-salt induced hypertensive rats. Eur J Pharmacol. 2012, 679(1–3):81-89.
• [42]Hermann M, Flammer A, Luscher TF: Nitric oxide in hypertension. J Clin Hypertens (Greenwich, Conn) 2006, 8(12 Suppl 4):17-29.
• [43]Santuzzi CH, Tiradentes RV, Mengal V, Claudio ERG, Mauad H, Gouvea SA, et al.: Combined aliskiren and L-arginine treatment has antihypertensive effects and prevents vascular endothelial dysfunction in a model of renovascular hypertension. Braz J Med Biol Res 2015, 48:65-76.
• [44]Amaral LM, Pinheiro LC, Guimaraes DA, Palei AC, Sertorio JT, Portella RL, et al.: Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre-eclampsia. J Cell Mol Med 2013, 17(10):1300-1307.
• [45]Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J, Tedgui A: Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation 1998, 97(16):1536-1539.
• [46]Li JM, Shah AM: Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 2004, 287(5):R1014-R1030.
• [47]Jia L, Li Y, Xiao C, Du J: Angiotensin II induces inflammation leading to cardiac remodeling. Front Biosci. 2012, 17:221-231.
• [48]Gray MO, Long CS, Kalinyak JE, Li HT, Karliner JS: Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts. Cardiovasc Res 1998, 40(2):352-363.
• [49]Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG: Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia. 2009, 52(4):691-697.
• [50]Noh H, King GL: The role of protein kinase C activation in diabetic nephropathy. Kidney Int 2007, 106:S49-S53.
• [51]Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, et al.: Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol 2000, 11(9):1656-1666.
• [52]Dunlop M: Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int Suppl 2000, 77:S3-S12.
• [53]Kolm-Litty V, Sauer U, Nerlich A, Lehmann R, Schleicher ED: High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J Clin Invest. 1998, 101(1):160-169.
• [54]Forbes JM, Coughlan MT, Cooper ME: Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 2008, 57(6):1446-1454.
• [55]Saraheimo M, Teppo AM, Forsblom C, Fagerudd J, Groop PH: Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients. Diabetologia 2003, 46(10):1402-1407.
• [56]DallaVestra M, Mussap M, Gallina P, Bruseghin M, Cernigoi AM, Saller A, et al.: Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes. J Am Soc Nephrol. 2005, 16(Suppl 1):S78-S82.
• [57]Nelson CL, Karschimkus CS, Dragicevic G, Packham DK, Wilson AM, O’Neal D, et al.: Systemic and vascular inflammation is elevated in early IgA and type 1 diabetic nephropathies and relates to vascular disease risk factors and renal function. Nephrol Dial Transpl 2005, 20(11):2420-2426.
• [58]Rivero A, Mora C, Muros M, Garcia J, Herrera H, Navarro-Gonzalez JF: Pathogenic perspectives for the role of inflammation in diabetic nephropathy. Clin Sci. 2009, 116(6):479-492.
• [59]Limand AK TG. Inflammation indiabeticnephropathy. Mediat Inflamm. 2012; 2012(Article ID 146154):12.
• [60]Doggrell SA, Brown L: Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res 1998, 39(1):89-105.
• [61]Gudbrandsen OA, Hultstrom M, Leh S, Monica Bivol L, Vagnes O, Berge RK, et al.: Prevention of hypertension and organ damage in 2-kidney, 1-clip rats by tetradecylthioacetic acid. Hypertension 2006, 48(3):460-466.
• [62]Li J, Xie ZZ, Tang YB: Genistein prevents myocardial hypertrophy in 2-kidney 1-clip renal hypertensive rats by restoring eNOS pathway. J Pharmacol. 2010, 86(4):240-248.
• [63]Joo KW, Kim S, Ahn SY, Chin HJ, Chae DW, Lee J, et al.: Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney. BMC Nephrol. 2013, 14:98. BioMed Central Full Text