Mitochondrial remodeling and ischemic protection by G protein–coupled receptor 35 agonists

Wyant, Gregory A.; Yu, Wenyu; Doulamis, IIias P.; Nomoto, Rio; Saeed, Mossab; Duignan, Thomas; McCully, James D.; Kaelin, William G.

doi:10.1126/science.abm1638

Cited by 63 publications

(60 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It also inhibits CD4 + cell differentiation to the Th17 phenotype via AHR ( Wirthgen et al, 2018 ; Walczak et al, 2020a , b ) and is an endogenous activator of GPR35 ( Wang et al, 2006 ; Mackenzie and Milligan, 2015 ; Resta et al, 2016 ; Figure 2 ). This may carry novel implications for understanding the roles of kynurenic acid as new consequences of GPR35 activation are discovered such as those involving mitochondrial functioning ( Wyant et al, 2022 ).…”

Section: An Integrated Kynurenine-cytokine Systemmentioning

confidence: 99%

An integrated cytokine and kynurenine network as the basis of neuroimmune communication

et al. 2022

View full text Add to dashboard Cite

Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of ‘tonic’ kynurenine pathway affecting baseline activity and the superimposed ‘phasic’ cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions.

show abstract

Section: An Integrated Kynurenine-cytokine Systemmentioning

confidence: 99%

An integrated cytokine and kynurenine network as the basis of neuroimmune communication

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In fact, reducing tryptophan intake is tantamount to reducing protein intake, which is all the more complicated as patients often already have protein intakes below the recommended level (1.2 g/kg/d) [30]. In addition, Wyant et al recently identified another tryptophan-derived UT, kynurenic acid, which plays a protective role against ischemia [31]. Reduced tryptophan intake could lead to a decrease in kynurenic acid and worsen ischemic disease, which is a major complication of CKD patients.…”

Section: Discussionmentioning

confidence: 99%

Protein/Fiber Index Modulates Uremic Toxin Concentrations in Hemodialysis Patients

Ebersolt

Machado

Mallmann

et al. 2022

Toxins

View full text Add to dashboard Cite

Background: Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), two uremic toxins (UTs), are associated with increased mortality in patients with chronic kidney disease (CKD). These toxins are produced by the microbiota from the diet and excreted by the kidney. The purpose of this study was to analyze the effect of diet on IS and PCS concentration in hemodialysis (HD) patients. Methods: We performed a prospective monocentric study using a seven-day diet record and determination of serum IS and PCS levels in HD patients. We tested the association between toxin concentrations and nutritional data. Results: A total of 58/75 patients (77%) completed the diet record. Mean caloric intake was 22 ± 9.2 kcal/kg/day. The protein/fiber index was 4.9 ± 1.8. No correlation between IS or PCS concentration and protein/fiber index was highlighted. In the 18 anuric patients (31%) in whom residual renal function could not affect toxin concentrations, IS and PCS concentrations were negatively correlated with fiber intake and positively correlated with the protein/fiber index. In a multivariate analysis, IS serum concentration was positively associated with the protein/fiber index (p = 0.03). Conclusions: A low protein/fiber index is associated with low concentrations of uremic toxins in anuric HD patients. Diets with an increased fiber intake must be tested to determine whether they reduce PCS and IS serum concentrations.

show abstract

“…In this regard, a number of potential KynA receptors have been reported in the literature ( 113 – 119 ). We showed that ischemic protection by KynA reflects its ability to activate the orphan receptor GPR35 ( 120 ). Once bound to KynA, GPR35 internalizes to mitochondria where, in an ATPIF1-dependent manner, it promotes the dimerization of ATP synthase and thereby prevents futile ATP consumption by ATP synthase under hypoxic conditions ( 120 ).…”

Section: Remote Ischemic Protectionmentioning

confidence: 99%

Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer

Kaelin¹

2022

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel–Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world.

show abstract

Mitochondrial remodeling and ischemic protection by G protein–coupled receptor 35 agonists

Cited by 63 publications

References 75 publications

An integrated cytokine and kynurenine network as the basis of neuroimmune communication

An integrated cytokine and kynurenine network as the basis of neuroimmune communication

Protein/Fiber Index Modulates Uremic Toxin Concentrations in Hemodialysis Patients

Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer

Contact Info

Product

Resources

About