The Therapeutic Strategies for Uremic Toxins Control in Chronic Kidney Disease

Lu, Ping-Hsun; Yu, Min‐Chien; Wei, Meng-Jiun; Kuo, Ko‐Lin

doi:10.3390/toxins13080573

Cited by 20 publications

(16 citation statements)

References 160 publications

(182 reference statements)

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“…CXCL1 has been shown to drive HSC activation and liver fibrosis [ 23 ]. IL-1α deficiency can reduce the risk of liver fibrosis in NASH by reducing the level of CXCL1 [ 24 ]. At the 12th hour after TAA (100 mg/kg) injection, Ly6ChiF4/80int macrophages had a higher distribution (Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting SYK of monocyte-derived macrophages regulates liver fibrosis via crosstalking with Erk/Hif1α and remodeling liver inflammatory environment

et al. 2021

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Liver fibrosis is a danger signal indicating a huge risk of liver cancer occurrence, but there is still no effective clinical means to regulate the progress of liver fibrosis. Although a variety of drugs targeting SYK have been developed for tumors and autoimmune diseases, the mechanism and specific efficacy of SYK’s role in liver fibrosis are not yet clear. Our studies based on chronic CCL4, bile duct ligation, and subacute TAA mouse models show that SYK in monocyte-derived macrophages (MoMFs) is fully dependent on phosphorylation of Erk to up-regulate the expression of Hif1α, thereby forming the crosstalk with SYK to drive liver fibrosis progress. We have evaluated the ability of the small molecule SYK inhibitor GS9973 in a variety of models. Contrary to previous impressions, high-frequency administration of GS9973 will aggravate CCL4-induced liver fibrosis, which is especially unsuitable for patients with cholestasis whose clinical features are bile duct obstruction. In addition, we found that inhibition of MoMFs SYK impairs the expression of CXCL1, on one hand, it reduces the recruitment of CD11bhiLy6Chi inflammatory cells, and on the other hand, it promotes the phenotype cross-dress process of pro-resolution MoMFs, thereby remodeling the chronic inflammatory environment of the fibrotic liver. Our further findings indicate that on the basis of the administration of CCR2/CCR5 dual inhibitor Cenicriviroc, further inhibiting MoMFs SYK may give patients with fibrosis additional benefits.

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Section: Resultsmentioning

confidence: 99%

Targeting SYK of monocyte-derived macrophages regulates liver fibrosis via crosstalking with Erk/Hif1α and remodeling liver inflammatory environment

et al. 2021

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“…CKD is caused by the end-stage development of many kidney diseases when the kidneys lose their basic functions, manifested by systemic metabolic dysfunction, abnormal urine and blood indicators, and a poor prognosis [ 1 , 23 ]. Therefore, replication of stable animal models of CKD and selection of positive drugs were key aspects of the search for drugs to combat CKD.…”

Section: Discussionmentioning

confidence: 99%

Panax notoginseng saponins alleviate damage to the intestinal barrier and regulate levels of intestinal microbes in a rat model of chronic kidney disease

Xie

Zheng

et al. 2022

Renal Failure

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Objectives Chronic kidney disease (CKD) is a long-term condition characterized by poor prognosis and a high mortality rate. Panax notoginseng saponins (PNS) are the main active ingredient of the traditional Chinese herb Panaxnotoginseng(Burk.)F.H.Chen , which has been widely reported to have various pharmacological effects. Here, we examined the effect of PNS on renal function and the modulation of intestinal flora and intestinal barrier in a rat model of adenine-induced CKD. Methods Adenine was used to establish a rat model of CKD, biochemical testing, histopathologic examination, ELISA, immunohistochemical assay, western blot assay, and fecal microbiota 16s rRNA analysis was used to test the effect of PNS on CKD rats. Results Adenine induced a significant decrease in glomerular filtration rate, an increase in urinary protein excretion rate, and pathological damage to renal tissue in CKD rats. TNF-α, MCP-1, IL-1β, IL-18, TMAO, and endotoxin levels were increased in the blood of the model rats. Application of PNS countered the effects of adenine, restoring the above parameters to the level observed in healthy rats. In addition, activation of the inflammatory proteins NF-κB (p65) and NLRP3 and the fibrosis-associated proteins α-SMA and smad3 were inhibited in the kidneys of CKD rats. Furthermore, PNS promoted the expression of the tight junction proteins Occludin and ZO-1, increased SIgA levels, strengthened intestinal immunity, reduced mechanical damage to the intestine, was reduced levels of DAO and D-LA. Our data suggest PNS may delay CKD by restoring gut microbiota, and through the subsequent generation of a microbial barrier and modulation of microbiota metabolites. Conclusions In conclusion, PNS may inhibit the development of inflammation and fibrosis in the kidney tissue through regulation of intestinal microorganisms and inhibition of the activation of pro-inflammatory and pro-fibrotic proteins in the kidney.

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“…Further studies are needed focusing on indoxyl sulfate mediated disturbance on the maturation, differentiation and viability of the T cells. A strategy to lower the systemic level of indoxyl sulfate, such as administration of AST-120 [39,42] or other conjunctive agents, such as resveratrol [43], might potentiate the efficacy of vaccines against SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

Indoxyl Sulfate Alters the Humoral Response of the ChAdOx1 COVID-19 Vaccine in Hemodialysis Patients

Hou

et al. 2022

Vaccines

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Background and aims: Vaccination for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is strongly recommended. The efficacy of SARS-CoV-2 vaccine for patients with end-stage renal disease is low. Indoxyl sulfate (IS) is a representative protein bound uremic toxin arousing immune dysfunction in CKD patients. It is unknown whether IS impairs the efficacy of vaccines for SARS-CoV-2. Materials and Methods: From 1 June 2021, to 31 December 2021, hemodialysis patients (n = 358) and a control group (n = 59) were eligible to receive the first dose of the ChAdOx1 COVID-19 vaccine. Titer measurements indicative of the humoral response (anti-S1 IgG and surrogate virus neutralization test (sVNT) results) and indoxyl sulfate concentration measurement were performed 4 weeks after ChAdOx1 vaccine injection. Results: The serum concentrations of anti-S1 IgG were 272 ± 1726 AU/mL and 2111 ± 4424 AU/mL in hemodialysis patients and control group (p < 0.05), respectively. The sVNT values were 26.8 ± 21.1% and 54.0 ± 20.2% in the hemodialysis and control groups (p < 0.05), respectively. There was a decreasing trend for the anti-S1 IgG titer from the lowest to highest quartile of IS (p < 0.001). The patients with higher concentrations of IS had lower sVNT (p for trend < 0.001). Conclusion: Hemodialysis patients had weaker humoral immunity after the first dose of the ChAdOx1 vaccine. Higher concentration of IS altered the development of anti-S1 antibodies and sVNT-measured neutralization.

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The Therapeutic Strategies for Uremic Toxins Control in Chronic Kidney Disease

Cited by 20 publications

References 160 publications

Targeting SYK of monocyte-derived macrophages regulates liver fibrosis via crosstalking with Erk/Hif1α and remodeling liver inflammatory environment

Targeting SYK of monocyte-derived macrophages regulates liver fibrosis via crosstalking with Erk/Hif1α and remodeling liver inflammatory environment

Panax notoginseng saponins alleviate damage to the intestinal barrier and regulate levels of intestinal microbes in a rat model of chronic kidney disease

Indoxyl Sulfate Alters the Humoral Response of the ChAdOx1 COVID-19 Vaccine in Hemodialysis Patients

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