Effect of Empagliflozin on Tacrolimus-Induced Pancreas Islet Dysfunction and Renal Injury

Jin, Jian; Jin, Long; Luo, Kun; Lim, Sun Woo; Chung, Byung Ha; Yang, Chul Woo

doi:10.1111/ajt.14316

Cited by 48 publications

(52 citation statements)

References 47 publications

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“…The histopathologic features of TAC-induced renal injury are arteriolar hyalinization, vasoconstriction, interstitial fibrosis (IF), tubular atrophy, and apoptosis [ 4 , 5 , 6 ]. The pathophysiologic mechanism remains unclear; however, several in vivo and in vitro studies have identified that inflammatory mediates and apoptosis are linked to TAC-induced nephropathy [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Renoprotective Effects of Alpha-1 Antitrypsin against Tacrolimus-Induced Renal Injury

Lim

et al. 2020

IJMS

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The protective effects of alpha-1 antitrypsin (AAT) in tacrolimus (TAC)-induced renal injury was evaluated in a rat model. The TAC group rats were subcutaneously injected with 2 mg/kg TAC every day for four weeks. The TAC with AAT group was cotreated with daily subcutaneous injections of TAC and intraperitoneal injections of AAT (80 mg/kg) for four weeks. The effects of AAT on TAC-induced renal injury were evaluated using serum biochemistry, histopathology, and Western blotting. The TAC injection significantly increased renal interstitial fibrosis, inflammation, and apoptosis as compared to the control treatment. The histopathological examination showed that cotreatment of TAC and AAT attenuated interstitial fibrosis (collagen, fibronectin, and α-SMA staining), and α-SMA expression in Western blotting was also decreased. Immunohistochemical staining for inflammation (osteopontin and ED-1 staining) revealed improved interstitial inflammation in the TAC with AAT group compared to that in the TAC group. The TAC treatment increased renal apoptosis compared to the control treatment, based on the results of increased immunohistochemical staining of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), increased caspase-3 activity, and lower Bcl-2 to Bad expression ratio. However, AAT cotreatment significantly changed these markers and consequently showed decreased apoptosis. AAT protects against TAC-induced renal injury via antifibrotic, anti-inflammatory, and antiapoptotic effects.

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Section: Introductionmentioning

confidence: 99%

Renoprotective Effects of Alpha-1 Antitrypsin against Tacrolimus-Induced Renal Injury

Lim

et al. 2020

IJMS

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“…This presumption may be supported by the lack of difference in cell survival or ROS production in in vitro studies of the two groups. It is well known that oxidative stress [4,24,25] and apoptosis [25][26][27] are common mechanisms of TAC-induced DM. To explain the improved hyperglycemia control by CoQ 10 -W, we evaluated the antioxidant and anti-apoptotic effects of CoQ 10 -W and CoQ 10 -L in TAC-induced pancreatic islet injury.…”

Section: Discussionmentioning

confidence: 99%

The therapeutic efficacy of water-soluble coenzyme Q10 in an experimental model of tacrolimus-induced diabetes mellitus

Quan

Luo

Sheng

et al. 2020

Korean J Intern Med

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Background/Aims: Coenzyme Q 10 (CoQ 10) has antioxidant effects and is commercially available and marketed extensively. However, due to its low bioavailability, its effects are still controversial. We developed a water-soluble CoQ 10-based micelle formulation (CoQ 10-W) and tested it in an experimental model of tacrolimus (TAC)-induced diabetes mellitus (DM). Methods: We developed CoQ 10-W from a glycyrrhizic-carnitine mixed layer CoQ 10 micelle preparation based on acyltransferases. TAC-induced DM rats were treated with either lipid-soluble CoQ 10 (CoQ 10-L) or CoQ 10-W for 4 weeks. Their plasma and pancreatic CoQ 10 concentrations were measured using liquid chromatography-tandem mass spectrometry. The therapeutic efficacies of CoQ 10-W and CoQ 10-L on TAC-induced DM were compared using functional and morphological parameters and their effects on cell viability and reactive oxygen species (ROS) production were also evaluated in cultured rat insulinoma cells. Results: The plasma CoQ 10 level was signif icantly increased in the CoQ 10-W group compared to that in the CoQ 10-L group. Intraperitoneal glucose tolerance tests and glucose-stimulated insulin secretion revealed that CoQ 10-W controlled hyperglycemia and restored insulin secretion significantly better than CoQ 10-L. The TAC-mediated decrease in pancreatic islet size was significantly attenuated by CoQ 10-W but not by CoQ10-L. TAC-induced oxidative stress and apoptosis were significantly more reduced by CoQ 10-W than CoQ 10-L. Electron microscopy revealed that CoQ 10-W restored TAC-induced attenuation in the number of insulin granules and the average mitochondrial area, unlike CoQ 10-L. In vitro studies showed that CoQ 10-L and CoQ 10-W both improved cell viability and reduced ROS production in TAC-treated islet cells to a similar extent. Conclusions: CoQ 10-W has better therapeutic efficacy than CoQ 10-L in TAC-induced DM.

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“…PTdM is considered an important side effect of Tac treatment (25). There are several studies where animal models have shown that different doses of Tac cause PTdM after organ or cell transplantation (26,27); however, most recent studies focused on islet cell injury (8,28). Peripheral tissue is a vital location of the glucose metabolism (29).…”

Section: Discussionmentioning

confidence: 99%

Altered expression of glucose metabolism associated genes in a tacrolimus‑induced post‑transplantation diabetes mellitus in rat model

Zhang

et al. 2019

Int J Mol Med

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Post-transplantation diabetes mellitus (PTdM) is a known side effect in transplant recipients administered with immunosuppressant drugs, such as tacrolimus (Tac). Although injury of islet cells is considered a major reason for Tac-induced PTdM, the involvement of insulin resistance in PTdM remains unknown. In the present study, expression levels of adipocytokines, glucose metabolism associated genes and peroxisome proliferator-activated receptor (PPAR)-γ in adipose, muscular and liver tissues from a rat model induced with Tac (1 mg/kg/day) were examined. Rats developed hyperglycemia and glucose intolerance after 10 days of Tac administration. A subgroup of diabetic rats was further treated with rosiglitazone (4 mg/kg), a PPAR-γ activator. Adipose, muscle and liver tissues were obtained on day 15 after induction and the results demonstrated that expression levels of adipocytokines, PPAR-γ and proteins in the insulin associated signaling pathway varied in the different groups. Rosiglitazone administration significantly improved hyperglycemia, glucose intolerance and expression levels of proteins associated with insulin signaling, as well as adipocytokines expression. The results of this study demonstrated that adipocytokines and PPAR-γ signaling may serve important roles in the pathogenesis of Tac-induced PTdM, which may provide a promising application in the treatment of PTdM in the future.

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Effect of Empagliflozin on Tacrolimus-Induced Pancreas Islet Dysfunction and Renal Injury

Cited by 48 publications

References 47 publications

Renoprotective Effects of Alpha-1 Antitrypsin against Tacrolimus-Induced Renal Injury

Renoprotective Effects of Alpha-1 Antitrypsin against Tacrolimus-Induced Renal Injury

The therapeutic efficacy of water-soluble coenzyme Q10 in an experimental model of tacrolimus-induced diabetes mellitus

Altered expression of glucose metabolism associated genes in a tacrolimus‑induced post‑transplantation diabetes mellitus in rat model

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