Endoplasmic reticulum stress participates in the pathophysiology of mercury-caused acute kidney injury

PubMedID: 31736398Acute exposure to mercury chloride (HgCl2) causes acute kidney injury (AKI). Some metals interfere with protein folding, leading to endoplasmic reticulum stress (ERS), and the activation of cell death mechanisms, but in the case of mercury, there is no knowledge about whether the ERS mediates tubular damage. This study aimed to determinate if HgCl2 causes an AKI course with temporary activation of ERS and if this mechanism is involved in kidney cell death. Male mice were intoxicated with 5 mg/kg HgCl2 and sacrificed after 24, 48, 72, and 96 h of mercury administration. The kidneys of euthanized mice were used to assess the renal function, oxidative stress, redox environment, antioxidant enzymatic system, cell death, and reticulum stress markers (PERK, ATF-6, and IRE1? pathways). The results indicate temporary-dependent renal dysfunction, oxidative stress, and an increase of glutathione-dependent enzymes involved in the bioaccumulation process of mercury, as well as the enhancement of caspase 3 activity along with IRE1a, GADD-153, and caspase 12 expressions. Mercury activates the PERK/eIF2? branch during the first 48 h. Meanwhile, the activation of PERK/ATF-4 branch allowed for ATF-4, ATF-6, and IRE1? pathways to enhance GADD-153. It led to the activation of caspases 12 and 3, which mediated the deaths of the tubular and glomerular cells. This study revealed temporary-dependent ERS present during AKI caused by HgCl2, as well as how it plays a pivotal role in kidney cell damage. © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.Secretaría de Investigación y Posgrado, Instituto Politécnico Nacional Consejo Nacional de Ciencia y TecnologíaEdgar Cano-Europa thanks COTEBAL-IPN for the support given this year for the realization of this project. The authors thank INSTITUTO POLITÉCNICO NACIONAL, SECRETARÍA DE INVESTIGACIÓN Y POSGRADO-IPN, and CONACyT for financial support. The researchers are fellows of EDI, COFAA, and SNI

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study

Background Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. Methods We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. Findings We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10–8; OR 1·19 [95% CI 1·12–1·26]) and VTN (rs704; p=2·75 × 10–9; OR 0·84 [0·79–0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10–8; OR 1·18 [1·12–1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15–3·82]; p=1·73 × 10–13). Interpretation We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis