URAT1 inhibition by ALPK1 is associated with uric acid homeostasis

Kuo, Tzer‐Min; Huang, Chung‐Ming; Tu, Hung-Pin; Ko, Albert Min-Shan; Wang, Shu-Jung; Lee, Chi‐Pin; Ko, Ying‐Chin

doi:10.1093/rheumatology/kew463

Cited by 11 publications

(11 citation statements)

References 20 publications

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“…The rs7442295 single nucleotide polymorphism or loss-of-function mutation in the solute carrier family (SLC) 2, facilitated glucose transporter member 9 (SLC2A9) gene encoding for GLUT9 which results in reduced secretion of urate into urine and increased absorption into the bloodstream [39,40]. A similar pattern of hyperuricemia has been reported in the rs475688, rs3825016, and rs11726117 polymorphisms of the SLC22A12 gene encoding for URAT1 which results in renal hypouricemia type 1 [41,42]. A similar outcome has been observed with the rs2231142 single nucleotide polymorphism of the BCRP gene encoding for ABCG2 in addition to defective intestinal urate excretion [43,44].…”

Section: Ua and Genetic Variationsmentioning

confidence: 90%

Uric acid in metabolic syndrome: Does uric acid have a definitive role?

Çöpür

Demiray

Kanbay

2022

European Journal of Internal Medicine

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Section: Ua and Genetic Variationsmentioning

confidence: 90%

Uric acid in metabolic syndrome: Does uric acid have a definitive role?

Çöpür

Demiray

Kanbay

2022

European Journal of Internal Medicine

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“…33 We have demonstrated abundant expression of ALPK1 in renal tubular cells of mice. 6 These shreds of evidence strongly suggest that ALPK1 enhances CCL2 and CCL5 expression through NFkB activation in hyperglycaemic conditions in renal tubular cells.…”

Section: Discussionmentioning

confidence: 95%

ALPK1 regulates streptozotocin‐induced nephropathy through CCL2 and CCL5 expressions

Lee

Nithiyanantham

Hsu

et al. 2019

J Cellular Molecular Medi

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ALPK1 is associated with chronic kidney disease, gout and type 2 diabetes mellitus. Raised renal ALPK1 level in patients with diabetes was reported. Accelerated fibrotic nephropathies were observed in hyperglycaemic mice with up‐regulated ALPK1. The aim of this study was to identify the mediators contributing to ALPK1 effect involving in nephropathies induction. The haematoxylin and eosin staining, Masson's trichrome and immunohistochemical analysis of ALPK1, NFkB, CCL2 and CCL5 were performed in the mice kidney. Cytokine antibody array analysis was performed in streptozotocin‐treated wild‐type mice (WT‐STZ) and streptozotocin‐treated ALPK1 transgenic mice (TG‐STZ). The ALPK1 levels were measured in mice kidney and in cultured cells. We found that the higher levels of renal CCL2/MCP‐1, CCL5/Rantes and G‐CSF expression in TG‐STZ compared with the WT‐STZ. Glucose increased ALPK1 expressions in monocytic THP1 and human kidney‐2 cells. The protein expression of ALPK1, NFkB and lectin was up‐regulated in glucose‐treated HK‐2 cells. Knockdown of ALPK1 reduced CCL2 and CCL5 mRNA levels, whereas overexpressed ALPK1 increased CCL2 and CCL5 in cultured kidney cells. Taken together, these results show that high glucose increases ALPK1 and chemokine levels in the kidney. Elevated ALPK1 expression enhances renal CCL2 and CCL5 expressions in vivo and in vitro. ALPK1 is a mediator for CCL2 and CCL5 chemokine up‐regulation involving in diabetic nephropathies induction.

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“…The variant p. (T237M) could represent an extreme phenotype of the same spectrum, where NLRP3 inflammasome activation mediated by an overactive ALPK1 kinase could trigger all the phenotypic aspects described in carriers of this variant. ALPK1 has never been implicated before in the periodic fever syndromes, but its role in the innate immunity is well established and previous genomic studies found an association, in some populations, between specific ALPK1 variants with gout [23,29,30], that is considered a polygenic autoinflammatory disease. Future analyses on additional patients, even with an extended autoinflammatory phenotypic spectrum and functional tests on mutated ALPK1 proteins, will help to identify a precise role for this gene in the recurrent fever phenotype.…”

Section: Discussionmentioning

confidence: 99%

Rare missense variants in the ALPK1 gene may predispose to periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome

et al. 2019

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PFAPA is an autoinflammatory syndrome characterized by periodic fever, aphthous stomatitis, sterile pharingitis, and adenitis, with an onset usually before the age of five. While the condition is most commonly sporadic, a few cases are familial and are usually compatible with an autosomal dominant (AD) transmission pattern, with reduced penetrance in some pedigrees. We performed exome analysis in a family where PFAPA was present in three relatives in two generations showing apparent AD segregation, identifying several rare and/or novel heterozygous variants in genes involved in the autoinflammatory pathway. Following segregation analysis of candidate variants, only one, c. 2770T>C p.(S924P) in the ALPK1 gene, was found to be consistently present in affected family members. ALPK1 is broadly expressed in different tissues and its protein is the intracellular kinase activated by the bacterial ADP-heptose bisphosphate that phosphorylates and activates TRAF-Interacting protein with Forkhead-Associated domain (TIFA) and triggers the immediate response to Gramnegative bacterial invasion. Sequencing analysis of 13 additional sporadic cases and 10 familial PFAPA cases identified two additional heterozygous missense variants c.1024G>C p.(D342H) and c.710C>T p.(T237M) in two sporadic patients, suggesting that rare variants in ALPK1 may represent a predisposing factor for recurrent periodic fever in a pediatric population.

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URAT1 inhibition by ALPK1 is associated with uric acid homeostasis

Abstract: Elevated ALPK1 expression decreased URAT1 expression. ALPK1 might prevent the impact of urate reuptake via SLC22A12 and appeared to be negatively associated with gout. ALPK1 is a potential repressor of URAT1 protein expression.

Cited by 11 publications

References 20 publications

Uric acid in metabolic syndrome: Does uric acid have a definitive role?

Uric acid in metabolic syndrome: Does uric acid have a definitive role?

ALPK1 regulates streptozotocin‐induced nephropathy through CCL2 and CCL5 expressions

Rare missense variants in the ALPK1 gene may predispose to periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome

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