SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate

Balzer, Michael S.; Rong, Song; Nordlohne, Johannes; Zemtsovski, Jan D.; Schmidt, Sonja; Stapel, Britta; Bartošová, Mária; Vietinghoff, Sibylle von; Haller, Hermann; Schmitt, Claus Peter; Shushakova, Nelli

doi:10.3390/biom10111573

Cited by 45 publications

(44 citation statements)

References 37 publications

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“…No GLUT-1 inhibitor is currently available for use in humans ( Reckeh and Waldmann, 2020 ). The presence of SGLT-2 has been shown in peritoneal mesothelial cells of humans and mice ( Balzer et al, 2020 ). Their expression was upregulated by glucose containing dialysis fluids, which was prevented by SGLT-2 inhibition.…”

Section: Prevention and Treatmentmentioning

confidence: 99%

Aging of the Peritoneal Dialysis Membrane

Krediet¹

2022

Front. Physiol.

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Long-term peritoneal dialysis as currently performed, causes structural and functional alterations of the peritoneal dialysis membrane. This decay is brought about by the continuous exposure to commercially available glucose-based dialysis solutions. This review summarizes our knowledge on the peritoneum in the initial phase of PD, during the first 2 years and the alterations in function and morphology in long-term PD patients. The pseudohypoxia hypothesis is discussed and how this glucose-induced condition can be used to explain all peritoneal alterations in long-term PD patients. Special attention is paid to the upregulation of hypoxia inducing factor-1 and the subsequent stimulation of the genes coding for glucose transporter-1 (GLUT-1) and the growth factors transforming growth factor-β (TGFβ), vascular endothelial growth factor (VEGF), plasminogen growth factor activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF). It is argued that increased pseudohypoxia-induced expression of GLUT-1 in interstitial fibroblasts is the key factor in a vicious circle that augments ultrafiltration failure. The practical use of the protein transcripts of the upregulated growth factors in peritoneal dialysis effluent is considered. The available and developing options for prevention and treatment are examined. It is concluded that low glucose degradation products/neutral pH, bicarbonate buffered solutions with a combination of various osmotic agents all in low concentration, are currently the best achievable options, while other accompanying measures like the use of RAAS inhibitors and tamoxifen may be valuable. Emerging developments include the addition of alanyl glutamine to the dialysis solution and perhaps the use of nicotinamide mononucleotide, available as nutritional supplement.

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Section: Prevention and Treatmentmentioning

confidence: 99%

Aging of the Peritoneal Dialysis Membrane

Krediet¹

2022

Front. Physiol.

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“…ROS destroy PMC mitochondrial membrane integrity and reduce mitochondrial membrane potential (MMP). Moreover, ROS production is accompanied by an increase in intracellular DNA oxidative damage markers such as 8-hydroxydeoxyguanosine (8-OHdG) and a decrease in antioxidants such as glutathione (GSH) (Balzer et al, 2020). Our results showed that in rat PMCs, LY294002 and rapamycin prevented the increase of ROS levels stimulated by high-glucose peritoneal dialysate, increased the activity of GPX and GSH, and reduced the production of 8-OHdG and MDA.…”

Section: Discussionmentioning

confidence: 68%

“…Recent data shows that the total number of PD patients is increasing at an average annual rate of approximately 18% in China (Wu et al, 2016), indicating that PD is gradually becoming one of the main dialysis methods for kidney failure patients. However, the efficiency of PD gradually decreases with the time of PD prolonged and ultrafiltration failure (UFF) finally occurs, resulting in structural remodelling of the peritoneum, and PF (Balzer et al, 2020). It is currently known that epithelialmesenchymal transition (EMT) is the initial pathological change in PF.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PI3K/AKT/mTOR Signalling Pathway Activates Autophagy and Suppresses Peritoneal Fibrosis in the Process of Peritoneal Dialysis

et al. 2022

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Peritoneal dialysis (PD) is an important part of replacement therapy for kidney failure. However, long-term PD treatment can cause peritoneal fibrosis. Autophagy may be involved in the pathological mechanism of peritoneal fibrosis (PF). Although autophagy is currently known to be involved in course of PF, its specific effects still lack in-depth research. In this experiment, a high-glucose (HG)-induced peritoneal fibrosis rat model was successfully established via intraperitoneal injection of HG peritoneal dialysate, and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the mechanistic target of rapamycin (mTOR) inhibitor rapamycin were used to treat peritoneal fibrosis rats. In addition, in vitro studies of high glucose-induced peritoneal fibrosis were performed using rat peritoneal mesothelial cells (PMCs). In vivo and in vitro experiments showed that LY294002 and rapamycin effectively inhibited the process of PF induced by high glucose. In addition, LY294002 and rapamycin were found to alleviate fibrosis by eliminating intracellular reactive oxygen species (ROS) levels, promoting the expression of the epithelial mesenchymal transdifferentiation proteins zonula occludens-1 (ZO-1) and E-cadherin, and inhibiting the expression of p-PI3K, PI3K, p-mTOR, mTOR, the fibroblast-specific proteins ferroptosis suppressor protein 1 (FSP1), and alpha-smooth muscle actin (α-SMA). Moreover, LY294002 and rapamycin promoted expression of autophagy-related proteins LC3-II/I, p62, and beclin-1. The current data indicated that inhibition of PI3K/AKT/mTOR signalling pathway activated autophagy and suppressed PF in the process of PD. Therefore, intervention in this signalling pathway may become a research goal for the prevention and treatment of PF, which has important clinical significance.

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“…SGLT2 inhibitors blocked TGF-β1-induced mRNA expression of thrombospondin 1 (THBS1), tenascinC(TNC), and platelet-derived growth factor subunit B (PDGF-B), which were key mediators of renal brosis and kidney disease progression in two human proximal tubular (PT) cell lines [21]. Dapagli ozin signi cantly reduced e uent TGF-β concentrations, peritoneal thickeningand brosis, resulting in improved ultra ltration in a mouse model of chronic peritoneal exposure to high-glucose dialysate [22].…”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitors attenuate nephrin loss and enhance TGF-β1 secretion in type 2 diabetes patients with albuminuria: A Randomized Clinical Trial

Tian

Chen

Liang

et al. 2022

Preprint

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Objective: To evaluate the effect of SGLT2 inhibitor (SGLT2i) on albuminuria, nephrin (NPH) and transforming-growth-factor-beta1 (TGF-β1) levels in urine and low-grade inflammation in type 2 diabetes (T2D ) patients.Methods: A randomized, blank-controlled clinical trial included 68 T2D patients and 10 controls. Based on the urinary albumin-to-creatinine ratio (UACR), 68 diabetic patients were stratified into three levels, UACR<30 mg/g, UACR≧30 mg/g to≦300 mg/g and UACR˃300 mg/g, who were randomized(1:1:1) to receive SGLT2i treatment for 12 weeks. The concentrations of NPH and TGF-β1 in urine were measured as indications of podocyte injury and renal fibrosis. Low-grade inflammation was assessed by the levels of IL-6, TNFα and hsCRP.Results: After 12 weeks of SGLT2i treatment, the levels of UACR and NPH decreased, UTGF-β1 increased in the T2D with microalbuminuria and macroalbuminuria groups, NPH (1.12[0.59,1.29] vs 0.71[0.41,1.07] ug/ml, P=0.022) and (1.29[0.99,1.96] vs 0.93[0.57,1.31] ug/ml, P=0.002), UTGF-β1 (4.88±1.31vs 7.27±1.21 pg/ml, P˂0.001) and (4.30±1.34 vs 6.78±2.59 pg/ml, P˂0.001), respectively. The changes in NPH were positively correlated with the UACR and negatively correlated with UTGF-β1 in T2D with albuminuria.Conclusions: SGLT2i alleviate nephrin loss and enhance TGF-β1 excretion in urine in T2DM with albuminuria. The anti-albuminuric effect of SGLT2i could be attributed to mitigating podocyte apoptosis and attenuating renal fibrosis.Trial registration:This clinical trial was registered on 15/10/2019, in ClinicalTrials.gov, and the registry number is NCT04127084.

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SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate

Cited by 45 publications

References 37 publications

Aging of the Peritoneal Dialysis Membrane

Aging of the Peritoneal Dialysis Membrane

Inhibition of PI3K/AKT/mTOR Signalling Pathway Activates Autophagy and Suppresses Peritoneal Fibrosis in the Process of Peritoneal Dialysis

SGLT2 inhibitors attenuate nephrin loss and enhance TGF-β1 secretion in type 2 diabetes patients with albuminuria: A Randomized Clinical Trial

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