Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury

Rasha Ezzat Mostafa , Azza Hassan Morsi, Gihan Farag Asaad

Abstract


Background and purpose: The clinical use of the chemotherapeutic drug, doxorubicin (DXR), is significantly limited by its extensive multi-organ toxicity. Dipeptidyl peptidase-4 (DPP4) is over-expressed in oxidative stress, inflammation and apoptosis. DPP4 inhibitors have proven pleiotropic effects. The study investigates the protective effects of some DDP4 inhibitors; namely, saxagliptin (SAX) and vildagliptin (VIL) against DXR-induced nephrotoxicity in rats.

Experimental approach: Forty rats were divided into 4 groups. Group I served as normal control. Nephrotoxicity was induced in the remaining 3 groups by single-DXR injection (15 mg/kg, i.p.). Groups III and IV administered oral SAX (10 mg/ kg) and VIL (10 mg/ kg) for 2 weeks.

Findings/Results: DXR-control rats showed deteriorated renal functions, elevated renal inflammatory parameters (tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and inducible nitric oxide synthase (iNOS)), up-regulated nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and significant tubulointerstitial injury manifested by elevated neutrophil gelatinase-associated lipocalin concentration and distorted renal histopathological pictures. Immunohistochemical studies showed increased iNOS and Bax positivity in renal tissues of DXR-control rats. Treatment with SAX and VIL significantly attenuated DXR-induced nephrotoxicity via alleviation of all the above-mentioned parameters when compared to DXR-control rats.

Conclusion and implications: The study elucidated the possible mechanisms beyond DXR-induced nephrotoxicity to be through inflammation plus tubulointerstitial injury. DXR nephrotoxicity has been linked to TNF-α, IL-1β, and NLRP3 inflammasome up-regulation and iNOS expression. The protective role of SAX and VIL in mitigating the tubular injury and inflammatory effects of DXR on renal tissues has been tested and proved.

 

 


Keywords


Doxorubicin; Saxagliptin; Vildagliptin; Nephrotoxicity; Inflammation; Tubulo-interstitial injury.

References


Makino Y, Fujita Y, Haneda M. Dipeptidyl peptidase-4 inhibitors in progressive kidney disease. Curr Opin Nephrol Hypertens. 2015;24(1):67-73.

DOI: 10.1097/MNH.0000000000000080.

Higashijima Y, Tanaka T, Yamaguchi J, Tanaka S, Nangaku M. Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury. Am J Physiol Renal Physiol. 2015;308(8):F878-F887.

DOI: 10.1152/ajprenal.00590.2014.

Tanaka T, Higashijima Y, Wada T, Nangaku M. The potential for renoprotection with incretin-based drugs. Kidney Int. 2014;86(4):701-711.

DOI: 10.1038/ki.2014.236.

Zoja C, Abbate M, Remuzzi G. Progression of renal injury toward interstitial inflammation and glomerular sclerosis is dependent on abnormal protein filtration. Nephrol Dial Transplant. 2015;30(5):706-712.

DOI: 10.1093/ndt/gfu261.

Jo CH, Kim S, Park JS, Kim GH. Anti-inflammatory action of sitagliptin and linagliptin in doxorubicin nephropathy. Kidney Blood Press Res. 2018;43(3):987-999.

DOI: 10.1159/000490688.

Helal MG, Zaki MMAF, Said E. Nephroprotective effect of saxagliptin against gentamicin-induced nephrotoxicity, emphasis on anti-oxidant, anti-inflammatory and anti-apoptic effects. Life Sci. 2018;208:64-71.

DOI: 10.1016/j.lfs.2018.07.021.

Thongnak L, Chatsudthipong V, Lungkaphin A. Mitigation of renal inflammation and endoplasmic reticulum stress by vildagliptin and statins in high-fat high-fructose diet-induced insulin resistance and renal injury in rats. Biochim Biophys Acta, Mol Cell Biol Lipids. 2020;1865(9):158755.

DOI: 10.1016/j.bbalip.2020.158755.

El-Agamy DS, Abo-Haded HM, Elkablawy MA. Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats. Exp Biol Med (Maywood). 2016;241(14):1577-1587.

DOI: 10.1177/1535370216643418.

Demir F, Demir M, Aygun H. Evaluation of the protective effect of edaravone on doxorubicin nephrotoxicity by [99m Tc] DMSA renal scintigraphy and biochemical methods. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(8):1383-1390.

DOI: 10.1007/s00210-020-01832-2.

Kelleni MT, Amin EF, Abdelrahman AM. Effect of metformin and sitagliptin on doxorubicin-induced cardiotoxicity in rats: impact of oxidative stress, inflammation, and apoptosis. J Toxicol. 2015;2015:424813,1-8.

DOI: 10.1155/2015/424813.

Gangadharan Komala M, Gross S, Zaky A, Pollock C, Panchapakesan U. Saxagliptin reduces renal tubulointerstitial inflammation, hypertrophy and fibrosis in diabetes. Nephrology (Carlton). 2016;21(5):423-431.

DOI: 10.1111/nep.12618.

Nagai K, Fukuno S, Otani K, Nagamine Y, Omotani S, Hatsuda Y, et al. Prevention of doxorubicin-induced renal toxicity by theanine in rats. Pharmacology. 2018;101(3-4):219-224.

DOI: 10.1159/000486625.

Demir F, Demir M, Aygun H. Evaluation of the protective effect of paricalcitol and vitamin D3 at doxorubicin nephrotoxicity in rats with 99mTechnetium-dimercaptosuccinic acid renal scintigraphy and biochemical methods. Hum Exp Toxicol. 2021;40(2):274-283.

DOI: 10.1177/0960327120950010.

Li W, He W, Xia P, Sun W, Shi M, Zhou Y, et al. Total extracts of Abelmoschus manihot L. attenuates adriamycin-induced renal tubule injury via suppression of ROS-ERK1/2-mediated NLRP3 inflammasome activation. Front Pharmacol. 2019;10:567-582.

DOI: 10.3389/fphar.2019.00567.

Maayah ZH, Takahara S, Dyck JR. The beneficial effects of reducing NLRP3 inflammasome activation in the cardiotoxicity and the anti-cancer effects of doxorubicin. Arch Toxicol. 2021;95(1):1-9.

DOI: 10.1007/s00204-020-02876-2.

Refaie MMM, Amin EF, El-Tahawy NF, Abdelrahman AM. Possible protective effect of diacerein on doxorubicin-induced nephrotoxicity in rats. J Toxicol. 2016;2016:9507563,1-10.

DOI: 10.1155/2016/9507563.

Rafiee Z, Moaiedi MZ, Gorji AV, Mansouri E. p-Coumaric acid mitigates doxorubicin-induced nephrotoxicity through suppression of oxidative stress, inflammation and apoptosis. Arch Med Res. 2020;51(1):32-40.

DOI: 10.1016/j.arcmed.2019.12.004.

Altınkaynak Y, Kural B, Akcan BA, Bodur A, Özer S, Yuluğ E, et al. Protective effects of L-theanine against doxorubicin-induced nephrotoxicity in rats. Biomed Pharmacother. 2018;108:1524-1534.

DOI: 10.1016/j.biopha.2018.09.171.

El‐Bialy BE, Abd Eldaim MA, Hassan A, Abdel‐Daim MM. Ginseng aqueous extract ameliorates lambda‐cyhalothrin‐acetamiprid insecticide mixture for hepatorenal toxicity in rats: role of oxidative stress‐mediated proinflammatory and proapoptotic protein expressions. Environ Toxicol. 2020;35(2):124-135.

DOI: 10.1002/tox.22848.

Hassan NF, Nada SA, Hassan A, El-Ansary MR, Al-Shorbagy MY, Abdelsalam RM. Saroglitazar deactivates the hepatic LPS/TLR4 signaling pathway and ameliorates adipocyte dysfunction in rats with high-fat emulsion/LPS model-induced non-alcoholic steatohepatitis. Inflammation. 2019;42(3):1056-1070.

DOI: 10.1007/s10753-019-00967-6.

Jalili C, Moradi D, Roshankhah S, Salahshoor MR. Effect of pentoxifylline on kidney damage induced by nitrosamine in male rats. Res Pharm Sci. 2019;14(1):64-73.

DOI: 10.4103/1735-5362.251854.

Abd El-Aziz TA, Mohamed RH, Pasha HF, Abdel-Aziz HR. Catechin protects against oxidative stress and inflammatory-mediated cardiotoxicity in adriamycin-treated rats. Clin Exp Med. 2012;12(4):233-240.

DOI: 10.1007/s10238-011-0165-2.

Tu Y, Sun W, Wan YG, Che XY, Pu HP, Yin XJ, et al. Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, ameliorates adriamycin-induced renal inflammation and glomerular injury via inhibiting p38MAPK signaling pathway activity in rats. J Ethnopharmacol. 2013;147(2):311-320.

DOI: 10.1016/j.jep.2013.03.006.

Sauter KA, Wood LJ, Wong J, Iordanov M, Magun BE. Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome: progress at a snail's pace. Cancer Biol Ther. 2011;11(12):1008-1016.

DOI: 10.4161/cbt.11.12.15540.

Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320(5876):674-677.

DOI: 10.1126/science.1156995.

Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509-513.

DOI: 10.1038/nature07710.

Jandhyala DM, Ahluwalia A, Obrig T, Thorpe CM. ZAK: a MAP3Kinase that transduces Shiga toxin‐and ricin‐induced proinflammatory cytokine expression. Cell Microbiol. 2008;10(7):1468-1477.

DOI: 10.1111/j.1462-5822.2008.01139.x.

Sauter KA, Magun EA, Iordanov MS, Magun BE. ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells. Cancer Biol Ther. 2010;10(3):258-266.

DOI: 10.4161/cbt.10.3.12367.

Devarajan P. Neutrophil gelatinase‐associated lipocalin (NGAL): a new marker of kidney disease. Scand J Clin Lab Invest Suppl. 2008;241:89-94.

DOI: 10.1080/00365510802150158.

Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, et al. Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol. 2007;18(2):407-413.

DOI: 10.1681/ASN.2006080882.

Szalay CI, Erdélyi K, Kökény G, Lajtár E, Godó M, Révész C, et al. Oxidative/nitrative stress and inflammation drive progression of doxorubicin-induced renal fibrosis in rats as revealed by comparing a normal and a fibrosis-resistant rat strain. PLoS One. 2015;10(6):e0127090,1-17.

DOI: 10.1371/journal.pone.0127090.

Schaub S, Wilkins JA, Nickerson P. Proteomics and renal transplantation: searching for novel biomarkers and therapeutic targets. Contrib Nephrol. 2008;160:65-75.

DOI: 10.1159/000125934.

Mostafa RE, Dalia OS, Dina FM. Cisplatin-induced nephrotoxicity in rats: modulatory role of simvastatin and rosuvastatin against apoptosis and inflammation. J Appl Pharm Sci. 2018;8(4):43-50.

DOI: 10.7324/JAPS.2018.8406.

Salama AAA, Mostafa RE, Omara EA. Ameliorative effects of phosphodiesterase (PDE) inhibitors in potassium dichromate-induced acute renal failure in rats. Int J Pharm Sci Rev Res. 2016;36(2):40-46.

Liu LL, Li QX, Xia L, Li J, Shao L. Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats. Toxicology. 2007;231(1):81-90.

DOI: 10.1016/j.tox.2006.11.067.

Ibrahim MA, Ashour OM, Ibrahim YF, El-Bitar HI, Gomaa W, Abdel-Rahim SR. Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity. Pharmacol Res. 2009;60(5):373-381.

DOI: 10.1016/j.phrs.2009.05.007.

Rehman MU, Tahir M, Khan AQ, Khan R, Oday-O-Hamiza, Lateef A, et al. D-limonene suppresses doxorubicin-induced oxidative stress and inflammation via repression of COX-2, iNOS, and NFκB in kidneys of Wistar rats. Exp Biol Med (Maywood). 2014;239(4):465-476.

DOI: 10.1177/1535370213520112.

Kumral A, Giriş M, Soluk-Tekkeşin M, Olgaç V, Doğru-Abbasoğlu S, Türkoğlu Ü, et al. Effect of olive leaf extract treatment on doxorubicin-induced cardiac, hepatic and renal toxicity in rats. Pathophysiology. 2015;22(2):117-123.

DOI: 10.1016/j.pathophys.2015.04.002.

Boulton DW. Clinical pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor. Clin Pharmacokinet. 2017;56(1):11-24.

DOI: 10.1007/s40262-016-0421-4.

He H, Tran P, Yin H, Smith H, Batard Y, Wang L, et al. Absorption, metabolism, and excretion of [14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Drug Metab Dispos. 2009;37(3):536-544.

DOI: 10.1124/dmd.108.023010.

Tarasova AP, Danilenko L, Tatarenkova IA, Khavanskii AV, Alena AA, Dovgan AP. Evaluation of cardioprotective effects of the incritin mimetics exenatide and vildagliptin in the experiment. Res Results Pharmacol. 2017;3(2):57-63.

DOI: 10.18413/2313-8971-2017-3-2-57-63.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.