Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Jo, Chor Ho; Kim, Sua; Park, Joon Sung; Kim, Gheun-Ho

doi:10.1159/000490688

Cited by 40 publications

(29 citation statements)

References 49 publications

(45 reference statements)

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“…In obese DIO mice, it is well documented that systemic dpp4 inhibitors exert anti-inflammatory properties [23, 24]. In our study with obese and hyperglycemic db/db mice, we were able to confirm that systemic dpp4 inhibition has anti-inflammatory effects.…”

Section: Discussionsupporting

confidence: 79%

A siRNA mediated hepatic dpp4 knockdown affects lipid, but not glucose metabolism in diabetic mice

Görgens

Jahn‐Hofmann

Bangari³

et al. 2019

PLoS ONE

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Systemic inhibition of dipeptidyl peptidase 4 (dpp4) represents an effective and established treatment option for type 2 diabetes (T2D). The current study investigated in mice if a liver selective knock-down of dpp4 by therapeutic siRNAs could be a novel, similarly effective treatment option for T2D. Furthermore, the potential effects on hepatic steatosis, inflammation and lipid metabolism were investigated after hepato-selective knock-down of dpp4. The knock-down efficiency and IC50 values of siRNAs targeting dpp4 were analyzed in PC3 cells. In two independent studies, either db/db mice or C57BL/6J mice were injected intravenously with a liposomal formulation of siRNAs targeting either dpp4 or a non-targeting control, followed by metabolically characterization. In comparator groups, additional cohorts of mice were treated with an oral dpp4 inhibitor. In both animal studies, we observed a robust knock-down (~75%) of hepatic dpp4 with a potent siRNA. Hepatic dpp4 knockdown did not significantly affect glucose metabolism or circulating incretin concentrations in both animal studies. However, in obese and diabetic db/db mice hepatic steatosis was reduced and hepatic mRNA expression of acaca, scd1, fasn and pparg was significantly lower after siRNA treatment. Systemic inhibition of the enzymatic dpp4 activity by an oral dpp4 inhibitor significantly improved glucose handling in db/db mice but did not affect hepatic endpoints. These data demonstrate that a targeted reduction of dpp4 expression in the liver may not be sufficient to improve whole-body glucose metabolism in obese and diabetic mice but may improve hepatic lipid metabolism.

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Section: Discussionsupporting

confidence: 79%

A siRNA mediated hepatic dpp4 knockdown affects lipid, but not glucose metabolism in diabetic mice

Görgens

Jahn‐Hofmann

Bangari³

et al. 2019

PLoS ONE

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“…Saxagliptin was previously shown to inhibit the AngII-induced activation of a range of cardiac proinflammatory/profibrotic signaling intermediates, including interleukin 18 (IL-18), interleukin 17A (IL-17A), nuclear transcription factor-κB (NF-κB), and TLR4 (39). Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) have been positively correlated with blood pressure (40, 41), and the inhibition of DPP-4 has been shown to down-regulate the expression of IL-6 and TNF-α (36, 42, 43). In contrast, Tinsley et al found that interleukin 10 (IL-10), released by Treg cells, has beneficial effects in terms of reducing inflammation, ameliorating endothelial function, and lowering BP in hypertensive pregnant rats (44).…”

Section: Dpp-4 Inhibitors and Bp Regulation: Potential Mechanismsmentioning

confidence: 99%

“…Moreover, many studies were performed to explore the deeper mechanism. For example, Jo et al showed that DPP-4i can restrain the activity of the nod-like receptor protein 3 (NLRP3) inflammasome by alleviating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2-associated oxidative stress (43). Hu et al further showed that the treatment of vascular endothelial cells with sitagliptin could inhibit the TNF-induced expression of vascular cell adhesion mole 1 (VCAM-1) mRNA (54).…”

Section: Dpp-4 Inhibitors and Bp Regulation: Potential Mechanismsmentioning

confidence: 99%

DPP-4 Inhibitors as Potential Candidates for Antihypertensive Therapy: Improving Vascular Inflammation and Assisting the Action of Traditional Antihypertensive Drugs

et al. 2019

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Dipeptidyl peptidase-4 (DPP-4) is an important protease that is widely expressed on the surface of human cells and plays a key role in immune-regulation, inflammation, oxidative stress, cell adhesion, and apoptosis by targeting different substrates. DPP-4 inhibitors (DPP-4i) are commonly used as hypoglycemic agents. However, in addition to their hypoglycemic effect, DPP-4i have also shown potent activities in the cardiovascular system, particularly in the regulation of blood pressure (BP). Previous studies have shown that the regulatory actions of DPP-4i in controlling BP are complex and that the mechanisms involved include the functional activities of the nerves, kidneys, hormones, blood vessels, and insulin. Recent work has also shown that inflammation is closely associated with the elevation of BP, and that the inhibition of DPP-4 can reduce BP by regulating the function of the immune system, by reducing inflammatory reactions and by improving oxidative stress. In this review, we describe the potential anti-hypertensive effects of DPP-4i and discuss potential new anti-hypertensive therapies. Our analysis indicated that DPP-4i treatment has a mild anti-hypertensive effect as a monotherapy and causes a significant reduction in BP when used in combined treatments. However, the combination of DPP-4i with high-dose angiotensin converting enzyme inhibitors (ACEI) can lead to increased BP. We suggest that DPP-4i improves vascular endothelial function in hypertensive patients by suppressing inflammatory responses and by alleviating oxidative stress. In addition, DPP-4i can also regulate BP by activating the sympathetic nervous system, interfering with the renin angiotensin aldosterone system (RAAS), regulating Na/H 2 O metabolism, and attenuating insulin resistance (IR).

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“…Currently, the anti‐inflammatory activity of Sita has been shown in various kinds of organ damage, for example, cardiovascular, hepatocellular and renal damage . Prominently, Sita has demonstrated nephroprotective action in experimental initiated nephropathy by means of regulation of lipid metabolism, oxidative stress (OS), and inflammatory mediators …”

Section: Introductionmentioning

confidence: 99%

Curcumin synergistically potentiates the protective effect of sitagliptin against chronic deltamethrin nephrotoxicity in rats: Impact on pro‐inflammatory cytokines and Nrf2/Ho‐1 pathway

Shi

Zhang

Wang

et al. 2019

J Biochem & Molecular Tox

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Deltamethrin (DLM) is a synthesized organophosphorus acaricide and bug spray, broadly utilized for veterinary and farming purposes. Although its exposure to humans and animals causes toxicity in the kidney and other primary organs, our objective was to assess the defensive effects of sitagliptin (Sita) and additionally curcumin (Cur) in the DLM‐intoxicated rats’ kidney. DLM‐intoxicated rats revealed a huge increase of various biochemical parameters in serum identified with kidney damage: uric acid, urea, and creatinine. DLM intoxication altogether increased renal lipid peroxidation, and critically restrained antioxidative biomarkers including superoxide dismutase, glutathione, and glutathione peroxidase. Likewise, it increased the tumor necrosis factor‐α, interleukin 6 (IL‐6) and IL‐1β level in serum. Additionally, DLM intoxication diminished the outflow of the nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2)/heme oxygenase‐1 (HO‐1) pathway in rats. Both Sita and Cur act against DLM‐prompted serum along with renal tissue biochemical parameters when utilized alone or in a mix alongside DLM intoxication. Besides this, both Sita and Cur delivered synergetic nephroprotective, antioxidative, and anti‐inflammatory impacts. Consequently, it could be presumed that Sita as well as Cur administration can limit the poisonous impacts of DLM by their free radical‐scavenging, strong antioxidant, and Nrf2/HO‐1 pathway upregulation activity.

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Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Cited by 40 publications

References 49 publications

A siRNA mediated hepatic dpp4 knockdown affects lipid, but not glucose metabolism in diabetic mice

A siRNA mediated hepatic dpp4 knockdown affects lipid, but not glucose metabolism in diabetic mice

DPP-4 Inhibitors as Potential Candidates for Antihypertensive Therapy: Improving Vascular Inflammation and Assisting the Action of Traditional Antihypertensive Drugs

Curcumin synergistically potentiates the protective effect of sitagliptin against chronic deltamethrin nephrotoxicity in rats: Impact on pro‐inflammatory cytokines and Nrf2/Ho‐1 pathway

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