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Sitagliptin Prevents Inflammation and Apoptotic Cell Death in the Kidney of Type 2 Diabetic Animals
Open accessAbstract
This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of type 2 diabetes mellitus; the Zucker diabetic fatty (ZDF) rat: 20-week-old rats were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia and bloodHbA1clevels were monitored, as well as kidney function and lesions. Kidney mRNA and/or protein content/distribution of DPP-IV, GLP-1, GLP-1R, TNF-α, IL-1β, BAX, Bcl-2, and Bid were evaluated by RT-PCR and/or western blotting/immunohistochemistry. Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia andHbA1c(by about 22.5% and 1.2%, resp.) and ameliorated tubulointerstitial and glomerular lesions. Sitagliptin prevented the diabetes-induced increase in DPP-IV levels and the decrease in GLP-1 levels in kidney. Sitagliptin increased colocalization of GLP-1 and GLP-1R in the diabetic kidney. Sitagliptin also decreased IL-1βand TNF-αlevels, as well as, prevented the increase of BAX/Bcl-2 ratio, Bid protein levels, and TUNEL-positive cells which indicates protective effects against inflammation and proapoptotic state in the kidney of diabetic rats, respectively. In conclusion, sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti-inflammatory and antiapoptotic properties.
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“emerging data suggest that GLP-1-based therapies also showed anti-inflammatory effects on the liver, vascular system including aorta and vein endothelial cells, brain, kidney, lung, testis, and skin by reducing the production of inflammatory cytokines and infiltration of immune cells in the tissues [17, 21–25].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [25]
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“Sitagliptin (10 mg/kg/day) treatment decreased the expression of proinflammatory cytokine genes IL-1β and TNF-α in kidney of diabetic ZDF rat [25].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [25]
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“Sitagliptin has been shown to prevent apoptotic cell death in the kidney of ZDF-rats, as indicated by reductions in the BAX/Bcl-2 ratio, Bid protein levels, and numbers of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in the kidney sections [98].”
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“On the other hand, GLP-1-dependent nephroprotective effects have been reported in STZ-induced and genetic diabetic rodent models (Liu et al. 2012; Marques et al. 2014).”
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“…that reported the capability of sitagliptin to improve kidney function and attenuate the histopathological changes in different experimental models such as diabetic nephropathy 114 , ischemia–reperfusion injury 34 , gentamicin nephrotoxicity 115 , and cisplatin-induced nephrotox-icity in mice 116 .”
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“Sitagliptin also has been shown to attenuate glomerulosclerosis and tubulointerstitial fibrosis by decreasing the levels of inflammatory cytokines such as IL-1β and TNF-α as well as cellular apoptosis in the kidney of ZDF rats [40].”
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Nephroprotective effect of Artemisia herba alba aqueous extract in alloxan-induced diabetic rats
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“Sitagliptin exerts a renoprotective effect against ischaemia– reperfusion injury through attenuating oxidative stress([18]) and also prevents apoptotic cell death in the kidney of type 2 diabetic animals.([19]) Moreover, sitagliptin improves the cardiac mitochondrial dysfunction([17]) and attenuates the brain mitochon…”
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“Similarly, DPP-IV inhibition by sitagliptin resulted in repressed renal inflammatory cascade, as witnessed through reduced TNF-a levels, which might justify the enhanced renal function and alleviation of renal lesions (Marques et al. 2014).”
BackgroundMitochondrion-driven nephroprotective mechanisms of novel glucose lowering medications
Afşar, B., Hornum, M., Afşar, R. E., Ertuğlu, L. A., Ortíz, A., Covic, A. C., van Raalte, D. H., Cherney, D. Z. I., & Kanbay, M. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.02.016 · Cited by 29
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“Therefore, by incr asing the concentration of active GLP-1, s tagliptin may synergistically reduce inflammation in abetic kidneys [44,45].”
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“Other authors found a decrease in the concentration of inflammatory and pro-fibrotic cytokines in animal models of diabetes treated with sitagliptin [130].”
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“Furthermore, the treatment of ZDF rats with sitagliptin also ameliorated nitrosative stress, inflammation and apoptosis in retinal cells, and prevented diabetic nephropathy progression through antiinflammatory and anti-apoptotic properties [44–46].”
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“SIT prevented the proapoptotic state and the increase in both mRNA and protein levels of proinflammatory cytokines, including TNF-α and others in diabetic kidneys of ZDF rats [50].”
BackgroundEffect of sitagliptin on tubulointerstitial Wnt/β‐catenin signalling in diabetic nephropathy
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“Marques et al.(22)confirmed that sitagliptin can attenuate the high expression of DPP-4, restore the biological activity of GLP-1, and further reduce proteinuria and pathological damage to the glomeruli and tubulointerstitial area in diabetic rats.”
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“These results are correlated with previous studies which reported anti-inflammatory effect of sitagliptin in different organs (Nader et al. 2012; El-Agamy et al. 2016) and, particularly, in the kidney organ (Li et al. 2014; Marques et al. 2014; Shalaby and Malek 2014; Chang et al. 2015).”
BackgroundResultInfluentialDiabetic Cardiomyopathy: Focus on Oxidative Stress, Mitochondrial Dysfunction and Inflammation
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“Interestingly, a linkage between diabetic glomerulopathy and crescent-like structures has already been pinpointed in Zucker diabetic fatty (ZDF) rats, a genetic T2DM animal model widely used in the preclinical setting as they spontaneously develop insulin resistance and obesity at a young age and progressively develop…”
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Dipeptidyl peptidase-4 inhibitors in progressive kidney disease
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“Recently, a study with similar experimental settings of low-dose sitagliptin administration for 6 weeks in ZDF rat demonstrated that sitagliptin prevented the tubulointerstitial and glomerular lesions [48].”
BackgroundResultChen, H., Zhang, X., Liao, N., Ji, Y., Mi, L., Gan, Y., Su, Y., & Wen, F. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1020252 · Cited by 13
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“Progressive hyperglycemia, a major feature of T2DM, contributes to the dysfunction of several organs, including the central and peripheral systems, eventually leading to diabetic complications [2,3].”
BackgroundKitada, M., Tsuda, S.-I., Konishi, K., Takeda‐Watanabe, A., Fujii, M., Kanasaki, K., Nishizawa, M., Nakagawa, A., & Koya, D. (2017) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2017-000391 · Cited by 12
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“Bax/Bcl2 is an indicator of response to the apoptotic signal and subsequent activation [43].”
BackgroundIncretin-based therapy: a new horizon in diabetes management
Zarei, M., Vaighan, N. S., Farjoo, M. H., Talebi, S., & Zarei, M. (2024) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-024-01479-3 · Cited by 12
“…], which offers DPP-4 as a marker of tubular injury in diseases and DPP-4 inhibitors through attenuating inflammatory cytokines and markers, such as IL-1β, TNF-α, chemoat - tractant protein-1 (MCP1), and high-sensitivity C-reactive protein (hs-CRP) in DKD cases and models [ 170, 174 , 199– 202].”
Eltahir, H. M., Elbadawy, H. M., Almikhlafi, M. A., Alalawi, A., Aldhafiri, A. J., Alahmadi, Y., Althagfan, S. S., Albadrani, M., Eweda, S. M., & Abouzied, M. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1389670 · Cited by 11
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“Moreover, studies have proposed that chronic inflammation characterizing obesity and T2DM may be traced to a common phenomenon: the upregulation of dipeptidyl peptidase 4 (DPP4), or cluster of differentiation 26 (CD26) in immune cell populations among adipocytes [7, 8].”
BackgroundResultRenoprotective Effects of Incretin‐Based Therapy in Diabetes Mellitus
Yaribeygi, H., Atkin, S. L., Montecucco, F., Jamialahmadi, T., & Sahebkar, A. (2021) · BioMed Research International · doi:10.1155/2021/8163153 · Cited by 14
“Moreover, Marques and coworkers in 2014 demonstrated that sitagliptin therapy attenuated the levels of IL-1β and TNF-α and decreased the inflammatory responses in kidneys in diabetic animals [55].”
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“found that low-dose sitagliptin ameliorated glomerular, tubulointerstitial, and vascular lesions in a T2D rat model of diabetic nephropathy.(31) Kodera et al.”
BackgroundSphingosine kinase 1–interacting protein is a dual regulator of insulin and incretin secretion
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Nephroprotection by Hypoglycemic Agents: Do We Have Supporting Data?
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“125 The B cell lymphoma-2 (BCL-2) family of proteins has a central role in modulating the intrinsic pathway of apoptosis through controlling mitochondrial permeability.”
BackgroundProtective effects of sitagliptin on methotrexate-induced nephrotoxicity in rats
Fard, L. A., Malekinejad, H., Esmaeilzadeh, Z., Jafari, A., Khezri, M. R., & Ghasemnejad‐Berenji, M. (2023) · Journal of Environmental Science and Health Part C · doi:10.1080/26896583.2023.2186683 · Cited by 6
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“Similarly, the DPP‐4 inhibitor linagliptin ameliorated DM‐induced kidney damage by inhibiting apoptosis (5).”
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DPP4 regulates the inflammatory response in a rat model of febrile seizures
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“Research carried out using type 2 DM animal models corroborate this effect of sitagliptin in hyperglycaemia.(25,35,36) For type 1 DM, the sitagliptin studies available in patients are not consistent.”
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“For example, in diabetic kidney disease, sitagliptin can reduce the degree of renal inflammation, including the expression of TNF-a, resulting in improved histological outcomes [144].”
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mTOR in Diabetic Nephropathy and Retinopathy
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“Previous investigations have similarly demonstrated that DPP-4 inhibition attenuates apoptosis-related signaling and preserves cellular integrity in experimental models of tissue injury (Abd-Eldayem et al. 2024; Marques et al. 2014).”
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Synergistic effects of sitagliptin and losartan against fipronil-induced hepatotoxicity in rats
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“This is contrary to reports from previous studies, where very low doses of ST (5 and 10 mg/kg) had produced decreases in serum levels of urea in diabetic rats.[26] The difference in the present study where ST was used in therapeutic doses is likely related to the extremely high urinary concentrations that result from…”
ResultInfluential
Metadata
- Authors
- Marques, C., Mega, C., Gonçalves, A., Rodrigues-Santos, P., Teixeira-Lemos, E., Teixeira, F., Fontes-Ribeiro, C., Reis, F., & Fernandes, R.
- Affiliations
- University of Coimbra (PT)
- Centro de Estudos em Educação Tecnologia e Saúde (PT)
- Institute of Immunology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Corresponding author
- Fernandes, Rosa
- ORCID
- Venue
- Mediators of Inflammation
- Publisher
- Wiley
- Published
- 2014
- Volume
- 2014
- Pages
- 1-15
- ISSN
- 0962-9351 (ISSN-L)
- 1466-1861
- PMC
- PMC4000968
- OpenAlex
- W2105771613
- Cited by
- 126
- References
- 80
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 15 · 2020: 15 · 2019: 10 · 2018: 11 · 2017: 21 · 2016: 15 · 2015: 8 · 2014: 1
- FWCI
- 12.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Mediators of Inflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by)
- Funders
- Foundation for Science and Technology, Portugal (PEst-C/SAU/UI3282/2011, PEst-C/SAU/UI3282/2013, COMPETE)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- sitagliptin, type 2 diabetes, diabetic nephropathy, DPP-4 inhibitors, glucagon-like peptide-1, GLP-1 receptor, renal inflammation, apoptosis, Bax/Bcl-2 ratio, Bid, TNF-α, IL-1β, tubulointerstitial injury, glomerular lesions, glycemic control, Zucker diabetic fatty rats
- MeSH terms
- Sitagliptin Phosphate, Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Inflammation, Kidney, Pyrazines, Rats, Zucker, Triazoles, Tumor Necrosis Factor-alpha, Apoptosis, Rats, Glucagon-Like Peptide 1, Dipeptidyl-Peptidase IV Inhibitors
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