The Novel Phosphate and Bile Acid Sequestrant Polymer SAR442357 Delays Disease Progression in a Rat Model of Diabetic Nephropathy

Castañeda, Tamara R.; Méndez, María Luisa Hevia; Davison, I. R.; Elvert, Ralf; Schwahn, Uwe; Boldina, Galina; Rocher, Corinne; Scherer, Petra; Singh, Kuldeep; Bangari, Dinesh S.; Falkenhahn, Mechthilde; Kannt, Aimo; Konkar, Anish; Larsen, Philip J.; Arbeeny, Cynthia M.; Dhal, Pradeep K.; Hübschle, Thomas

doi:10.1124/jpet.120.000285

Cited by 11 publications

(8 citation statements)

References 83 publications

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“…Indeed, the disorder of bile acid metabolism exists in DKD patients ( 10 , 51 ). The change in bile acids induced by medication has also been reported to be correlated with better clinical outcomes, thereby improving the metabolic health of DKD ( 52 , 53 ). In addition, DAPA could function by reducing the generation of ROS ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice

Chen²,

Yang³

et al. 2023

Front. Endocrinol.

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BackgroundThe intestinal microbiota disorder gradually aggravates during the progression of diabetes. Dapagliflozin (DAPA) can improve diabetes and diabetic kidney disease(DKD). However, whether the gut microbiota plays a role in the protection of DAPA for DKD remains unclear.MethodsTo investigate the effects of DAPA on DKD and gut microbiota composition during disease progression, in our study, we performed 16S rRNA gene sequencing on fecal samples from db/m mice (control group), db/db mice (DKD model group), and those treated with DAPA (treat group) at three timepoints of 14weeks\18weeks\22weeks.ResultsWe found that DAPA remarkably prevented weight loss and lowered fasting blood glucose in db/db mice during disease progression, eventually delaying the progression of DKD. Intriguingly, the study strongly suggested that there is gradually aggravated dysbacteriosis and increased bile acid during the development of DKD. More importantly, comparisons of relative abundance at the phylum level and partial least squares-discriminant analysis (PLS-DA) plots roughly reflected that the effect of DAPA on modulating the flora of db/db mice increased with time. Specifically, the relative abundance of the dominant Firmicutes and Bacteroidetes was not meaningfully changed among groups at 14 weeks as previous studies described. Interestingly, they were gradually altered in the treat group compared to the model group with a more protracted intervention of 18 weeks and 22 weeks. Furthermore, the decrease of Lactobacillus and the increase of norank_f:Muribaculaceae could account for the differences at the phylum level observed between the treat group and the model group at 18 weeks and 22 weeks.ConclusionWe firstly found that the protective effect of DAPA on DKD may be related to the dynamic improvement of the gut microbiota over time, possibly associated with the impact of DAPA on the bile acid pool and its antioxidation effect.

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Section: Discussionmentioning

confidence: 99%

Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice

Chen²,

Yang³

et al. 2023

Front. Endocrinol.

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“…SAR442357 is a newly developed non-absorbable polymeric sequestering agent with optimal phosphate and bile salt sequestration properties. Long-term treatment of diabetes mellitus type 2(T2DM) obese Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) leads to enhanced segregation of BAs and phosphates in the gut, improved glycemic control, reduced serum CHOL, and delayed DKD progression ( 199 ).…”

Section: Targeting Lipid Metabolism For Dkd Treatmentmentioning

confidence: 99%

Lipid metabolism disorder in diabetic kidney disease

Han,

Du,

Zhu

et al. 2024

Front. Endocrinol.

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Diabetic kidney disease (DKD), a significant complication associated with diabetes mellitus, presents limited treatment options. The progression of DKD is marked by substantial lipid disturbances, including alterations in triglycerides, cholesterol, sphingolipids, phospholipids, lipid droplets, and bile acids (BAs). Altered lipid metabolism serves as a crucial pathogenic mechanism in DKD, potentially intertwined with cellular ferroptosis, lipophagy, lipid metabolism reprogramming, and immune modulation of gut microbiota (thus impacting the liver-kidney axis). The elucidation of these mechanisms opens new potential therapeutic pathways for DKD management. This research explores the link between lipid metabolism disruptions and DKD onset.

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“…Long-term treatment of T2DM obese ZSF1 rats with another BAS, SAR442357, increased plasma insulin levels and decreased HbA1c, cholesterol, and triglyceride levels ( Supplementary Table S1 ). Unlike Colesevelam hydrochloride, SAR442357 also slows the progression of diabetic kidney disease (DKD) ( Castañeda et al, 2021 ).…”

Section: Therapeutic Effects Of Bile Acids and Their Derivatives On T...mentioning

confidence: 99%

Bile acids-gut microbiota crosstalk contributes to the improvement of type 2 diabetes mellitus

Gao

Meng²,

Xue³

et al. 2022

Front. Pharmacol.

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Type 2 diabetes mellitus (T2DM) occurs that cannot effectively use the insulin. Insulin Resistance (IR) is a significant characteristic of T2DM which is also an essential treatment target in blood glucose regulation to prevent T2DM and its complications. Bile acids (BAs) are one group of bioactive metabolites synthesized from cholesterol in liver. BAs play an important role in mutualistic symbiosis between host and gut microbiota. It is shown that T2DM is associated with altered bile acid metabolism which can be regulated by gut microbiota. Simultaneously, BAs also reshape gut microbiota and improve IR and T2DM in the bidirectional communications of the gut-liver axis. This article reviewed the findings on the interaction between BAs and gut microbiota in improving T2DM, which focused on gut microbiota and its debinding function and BAs regulated gut microbiota through FXR/TGR5. Meanwhile, BAs and their derivatives that are effective for improving T2DM and other treatments based on bile acid metabolism were also summarized. This review highlighted that BAs play a critical role in the glucose metabolism and may serve as therapeutic targets in T2DM, providing a reference for discovering and screening novel therapeutic drugs.

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The Novel Phosphate and Bile Acid Sequestrant Polymer SAR442357 Delays Disease Progression in a Rat Model of Diabetic Nephropathy

Cited by 11 publications

References 83 publications

Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice

Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice

Lipid metabolism disorder in diabetic kidney disease

Bile acids-gut microbiota crosstalk contributes to the improvement of type 2 diabetes mellitus

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