Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney

BMC Nephrology

Ki Young Na¹  Jin Suk Han²  Jeonghwan Lee³  Dong-Wan Chae¹  Ho Jun Chin¹  Shin-young Ahn¹  Sejoong Kim¹  Kwon Wook Joo² 

[1] Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, South Korea;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea;Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea

关键词: Kidney injury;    Sitagliptin;    FoxO3a;    Glucagon-like peptide-1 receptor;    Dipeptidyl peptidase IV;   

Others  :  1082941
DOI  :  10.1186/1471-2369-14-98

 received in 2012-10-26, accepted in 2013-04-24,  发布年份 2013

【 摘 要 】

Background

The inhibition of dipeptidyl peptidase (DPP) IV shows protective effects on tissue injury of the heart, lung, and kidney. Forkhead box O (FoxO) transcriptional factors regulate cellular differentiation, growth, survival, the cell cycle, metabolism, and oxidative stress. The aims of this study were to investigate whether the DPP IV inhibitor sitagliptin could attenuate kidney injury and to evaluate the status of FoxO3a signaling in the rat remnant kidney model.

Methods

Rats were received two-step surgery of 5/6 renal mass reduction and fed on an oral dose of 200 mg/kg/day sitagliptin for 8 weeks. Before and after the administration of sitagliptin, physiologic parameters were measured. After 8 weeks of treatment, the kidneys were harvested.

Results

The sitagliptin treatment attenuated renal dysfunction. A histological evaluation revealed that glomerulosclerosis and tubulointerstitial injury were significantly decreased by sitagliptin. Sitagliptin decreased DPP IV activity and increased the renal expression of glucagon-like peptide-1 receptor (GLP-1R). The subtotal nephrectomy led to the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and FoxO3a phosphorylation, whereas sitagliptin treatment reversed these changes, resulting in PI3K-Akt pathway inactivation and FoxO3a dephosphorylation. The renal expression of catalase was increased and the phosphorylation of c-Jun N-terminal kinase (JNK) was decreased by sitagliptin. Sitagliptin treatment reduced apoptosis by decreasing cleaved caspase-3 and −9 and Bax levels and decreased macrophage infiltration.

Conclusions

In rat remnant kidneys, DPP IV inhibitor attenuated renal dysfunction and structural damage. A reduction of apoptosis, inflammation and an increase of antioxidant could be suggested as a renoprotective mechanism together with the activation of FoxO3a signaling. Therefore, DPP IV inhibitors might provide a promising approach for treating CKD, but their application in clinical practice remains to be investigated.

【 授权许可】

   
2013 Joo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Baggio LL, Drucker DJ: Biology of incretins: GLP-1 and GIP. Gastroenterology 2007, 132:2131-2157.
• [2]Mentlein R: Dipeptidyl-peptidase IV (CD26)–role in the inactivation of regulatory peptides. Regul Pept 1999, 85:9-24.
• [3]Drucker DJ, Nauck MA: The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006, 368:1696-1705.
• [4]Park CW, Kim HW, Ko SH, Lim JH, Ryu GR, Chung HW, Han SW, Shin SJ, Bang BK, Breyer MD, Chang YS: Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J Am Soc Nephrol 2007, 18:1227-1238.
• [5]Kodera R, Shikata K, Kataoka HU, Takatsuka T, Miyamoto S, Sasaki M, Kajitani N, Nishishita S, Sarai K, Hirota D, Sato C, Ogawa D, Makino H: Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia 2011, 54:965-978.
• [6]Mega C, de Lemos ET, Vala H, Fernandes R, Oliveira J, Mascarenhas-Melo F, Teixeira F, Reis F: Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat). Exp Diabetes Res 2011.
• [7]Liu WJ, Xie SH, Liu YN, Kim W, Jin HY, Park SK, Shao YM, Park TS: Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats. J Pharmacol Exp Ther 2012, 340:248-255.
• [8]Glorie LL, Verhulst A, Matheeussen V, Baerts L, Magielse J, Hermans N, D'Haese PC, De Meester I, De Beuf A: DPP4 inhibition improves functional outcome after renal ischemia reperfusion injury. Am J Physiol Renal Physiol 2012, 303:F681-F688.
• [9]Lim SB, Rubinstein I, Sadikot RT, Artwohl JE, Önyüksel H: A novel peptide nanomedicine against acute lung injury: GLP-1 in phospholipid micelles. Pharm Res 2011, 28:662-672.
• [10]Jungraithmayr W, De Meester I, Matheeussen V, Baerts L, Arni S, Weder W: CD26/DPP-4 inhibition recruits regenerative stem cells via stromal cell-derived factor-1 and beneficially influences ischaemia-reperfusion injury in mouse lung transplantation. Eur J Cardiothorac Surg 2012, 41:1166-1173.
• [11]Zhai W, Jungraithmayr W, De Meester I, Inci I, Augustyns K, Arni S, Hillinger S, Scharpé S, Weder W, Korom S: Primary graft dysfunction in lung transplantation: the role of CD26/dipeptidylpeptidase IV and vasoactive intestinal peptide. Transplantation 2009, 87:1140-1146.
• [12]Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, Baggio LL, Henkelman RM, Husain M, Drucker DJ: GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 2009, 58:975-983.
• [13]Sauvé M, Ban K, Momen MA, Zhou YQ, Henkelman RM, Husain M, Drucker DJ: Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes after myocardial infarction in mice. Diabetes 2010, 59:1063-1073.
• [14]Remuzzi G, Bertani T: Pathophysiology of progressive nephropathies. N Engl J Med 1998, 339:1448-1456.
• [15]Fogo AB: Animal models of FSGS: lessons for pathogenesis and treatment. Semin Nephrol 2003, 23:161-171.
• [16]Zhang X, Tang N, Hadden TJ, Rishi AK: Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 1813, 2011:1978-1986.
• [17]Tzivion G, Dobson M, Ramakrishnan G: FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta 1813, 2011:1938-1945.
• [18]Jacobs FM, van der Heide LP, Wijchers PJ: FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 2003, 278:35959-35967.
• [19]Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA: Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther 2006, 28:55-72.
• [20]Weir GC, Mojsov S, Hendrick GK, Habener JF: Glucagonlike peptide I (7–37) actions on endocrine pancreas. Diabetes 1989, 38:338-342.
• [21]Schlatter P, Beglinger C, Drewe J, Gutmann H: Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regul Pept 2007, 141:120-128.
• [22]Chaykovska L, von Websky K, Rahnenführer J, Alter M, Heiden S, Fuchs H, Runge F, Klein T, Hocher B: Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy. PLoS One 2011, 6:e27861.
• [23]Lim S, Choi SH, Shin H, Cho BJ, Park HS, Ahn BY, Kang SM, Yoon JW, Jang HC, Kim YB, Park KS: Effect of a dipeptidyl peptidase-IV inhibitor, des-fluoro-sitagliptin, on neointimal formation after balloon injury in rats. PLoS One 2012, 7:e35007.
• [24]Kim JJ, Li P, Huntley J, Chang JP, Arden KC, Olefsky JM: FoxO1 haploinsufficiency protects against high-fat diet-induced insulin resistance with enhanced peroxisome proliferator-activated receptor gamma activation in adipose tissue. Diabetes 2009, 58:1275-1282.
• [25]Fang CX, Dong F, Thomas DP, Ma H, He L, Ren J: Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription. Am J Physiol Heart Circ Physiol 2008, 295:H1206-H1215.
• [26]Kim W, Egan JM: The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev 2008, 60:470-512.
• [27]Percy CJ, Brown L, Power DA, Johnson DW, Gobe GC: Obesity and hypertension have differing oxidant handling molecular pathways in age-related chronic kidney disease. Mech Ageing Dev 2009, 130:129-138.
• [28]Chung HW, Lim JH, Kim MY, Shin SJ, Chung S, Choi BS, Kim HW, Kim YS, Park CW, Chang YS: High-fat diet-induced renal cell apoptosis and oxidative stress in spontaneously hypertensive rat are ameliorated by fenofibrate through the PPARα-FoxO3a-PGC-1α pathway. Nephrol Dial Transplant 2012, 27:2213-2225.
• [29]Vaziri ND, Oveisi F, Ding Y: Role of increased oxygen free radical activity in the pathogenesis of uremic hypertension. Kidney Int 1998, 53:1748-1754.
• [30]Miyata T, Kurokawa K, Van Ypersele De Strihou C: Advanced glycation and lipoxidation end products: role of reactive carbonyl compounds generated during carbohydrate and lipid metabolism. J Am Soc Nephrol 2000, 11:1744-1752.
• [31]Fridovich I: Superoxide radical and superoxide dismutases. Annu Rev Biochem 1995, 64:97-112.
• [32]Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ: Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 2003, 278:471-478.
• [33]During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN: Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 2003, 9:1173-1179.
• [34]Zhang Y, Wang Q, Zhang J, Lei X, Xu GT, Ye W: Protection of exendin-4 analogue in early experimental diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2009, 247:699-706.
• [35]Marzioni M, Alpini G, Saccomanno S, Candelaresi C, Venter J, Rychlicki C, Fava G, Francis H, Trozzi L, Benedetti A: Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis. Gut 2009, 58:990-997.
• [36]Qin Z, Sun Z, Huang J, Hu Y, Wu Z, Mei B: Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid-beta peptide (1–42). Neurosci Lett 2008, 444:217-221.
• [37]Liu JH, Yin F, Guo LX, Deng XH, Hu YH: Neuroprotection of geniposide against hydrogen peroxide induced PC12 cells injury: involvement of PI3 kinase signal pathway. Acta Pharmacol Sin 2009, 30:159-165.
• [38]Kimura R, Okouchi M, Fujioka H, Ichiyanagi A, Ryuge F, Mizuno T, Imaeda K, Okayama N, Kamiya Y, Asai K, Joh T: Glucagon-like peptide-1 (GLP-1) protects against methylglyoxal-induced PC12 cell apoptosis through the PI3K/Akt/mTOR/GCLc/redox signaling pathway. Neuroscience 2009, 162:1212-1219.
• [39]Quoyer J, Longuet C, Broca C, Linck N, Costes S, Varin E, Bockaert J, Bertrand G, Dalle S: GLP-1 mediates antiapoptotic effect by phosphorylating Bad through a beta-arrestin 1-mediated ERK1/2 activation in pancreatic beta-cells. J Biol Chem 2010, 285:1989-2002.
• [40]Ravassa S, Zudaire A, Carr RD, Díez J: Antiapoptotic effects of GLP-1 in murine HL-1 cardiomyocytes. Am J Physiol Heart Circ Physiol 2011, 300:H1361-H1372.
• [41]Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, Fujitani Y, Hirose T, Kawamori R, Watada H: Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 2010, 59:1030-1037.