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Clinical Journal of the American... Mar 2022
Topics: Calcium; Calcium Oxalate; Female; Humans; Inflammation; Male; Nephrolithiasis
PubMed: 35078783
DOI: 10.2215/CJN.00510122 -
Plant Signaling & Behavior Dec 2022The ability to biosynthesize oxalic acid can provide beneficial functions to plants; however, uncontrolled or prolonged exposure to this strong organic acid results in...
The ability to biosynthesize oxalic acid can provide beneficial functions to plants; however, uncontrolled or prolonged exposure to this strong organic acid results in multiple physiological problems. Such problems include a disruption of membrane integrity, mitochondrial function, metal chelation, and free radical formation. Recent work suggests that a CoA-dependent pathway of oxalate catabolism plays a critical role in regulating tissue oxalate concentrations in plants. Although this CoA-dependent pathway of oxalate catabolism is important, large gaps in our knowledge of the enzymes catalyzing each step remain. Evidence that an oxalyl-CoA decarboxylase (OXC) catalyzes the second step in this pathway, accelerating the conversion of oxalyl-CoA to formyl-CoA, has been reported. Induction studies revealed that OXC gene expression was upregulated in response to an exogenous oxalate supply. Phylogenetic analysis indicates that OXCs are conserved across plant species. Evolutionarily the plant OXCs can be separated into dicot and monocot classes. Multiple sequence alignments and molecular modeling suggest that OXCs have similar functionality with three conserved domains, the N-terminal PYR domain, the middle R domain, and the C-terminal PP domain. Further study of this CoA-dependent pathway of oxalate degradation would benefit efforts to develop new strategies to improve the nutrition quality of crops.
Topics: Acyl Coenzyme A; Carboxy-Lyases; Models, Molecular; Oxalates; Oxalic Acid; Phylogeny
PubMed: 35510715
DOI: 10.1080/15592324.2022.2062555 -
Communications Biology Mar 2023Hyperoxaluria is well known to cause renal injury and end-stage kidney disease. Previous studies suggested that acetate treatment may improve the renal function in...
Hyperoxaluria is well known to cause renal injury and end-stage kidney disease. Previous studies suggested that acetate treatment may improve the renal function in hyperoxaluria rat model. However, its underlying mechanisms remain largely unknown. Using an ethylene glycol (EG)-induced hyperoxaluria rat model, we find the oral administration of 5% acetate reduced the elevated serum creatinine, urea, and protected against hyperoxaluria-induced renal injury and fibrosis with less infiltrated macrophages in the kidney. Treatment of acetate in renal tubular epithelial cells in vitro decrease the macrophages recruitment which might have reduced the oxalate-induced renal tubular cells injury. Mechanism dissection suggests that acetate enhanced acetylation of Histone H3 in renal tubular cells and promoted expression of miR-493-3p by increasing H3K9 and H3K27 acetylation at its promoter region. The miR-493-3p can suppress the expression of macrophage migration inhibitory factor (MIF), thus inhibiting the macrophages recruitment and reduced oxalate-induced renal tubular cells injury. Importantly, results from the in vivo rat model also demonstrate that the effects of acetate against renal injury were weakened after blocking the miR-493-3p by antagomir treatment. Together, these results suggest that acetate treatment ameliorates the hyperoxaluria-induced renal injury via inhibiting macrophages infiltration with change of the miR-493-3p/MIF signals. Acetate could be a new therapeutic approach for the treatment of oxalate nephropathy.
Topics: Animals; Rats; Acetates; Hyperoxaluria; Intramolecular Oxidoreductases; Kidney; Macrophage Migration-Inhibitory Factors; MicroRNAs; Oxalates
PubMed: 36922584
DOI: 10.1038/s42003-023-04649-w -
Genetics in Medicine : Official Journal... Mar 2023Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for...
PURPOSE
Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.
METHODS
Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.
RESULTS
Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca uptake, demonstrating loss of function.
CONCLUSION
Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.
Topics: Humans; Calcium Oxalate; Nephrolithiasis; Mutation, Missense; Sulfate Transporters; Receptors, Purinergic P2
PubMed: 36571463
DOI: 10.1016/j.gim.2022.11.019 -
Scientific Reports Mar 2022The role of the gut microbiome in the development of renal stone diseases has not been well characterized. This study focused on the taxonomic and functional profiles of...
The role of the gut microbiome in the development of renal stone diseases has not been well characterized. This study focused on the taxonomic and functional profiles of gut microbiomes according to the prevalence and incidence of nephrolithiasis. Stool samples from 915 Korean adults were collected at baseline. Participants were followed for a median of 4.0 years. We evaluated the biodiversity of the gut microbiota and taxonomic profiles associated with nephrolithiasis status, using 16S rRNA gene sequencing. Nephrolithiasis status was categorized into three groups: control (no-stone at both baseline and follow-up visits), incidental nephrolithiasis, and prevalent nephrolithiasis. Compared to the control and incidental nephrolithiasis, the prevalent nephrolithiasis showed a reduced evenness in alpha diversity. Nephrolithiasis was associated with a reduced abundance of some key taxa involved in short-chain fatty acid production. Moreover, the abundance of Bifidobacterium, which possess oxalate-degrading ability, was higher in the control. Conversely, there was no significant difference in the bacterial composition between the incidental and prevalent nephrolithiasis. In our study with repeated nephrolithiasis measurements, prevalent renal stones were associated with an altered gut microbiota composition compared to the control. Besides the known oxalate degradation pathway, other functional pathways inferred in this study require further investigation.
Topics: Adult; Female; Gastrointestinal Microbiome; Humans; Incidence; Kidney Calculi; Male; Oxalates; Prevalence; RNA, Ribosomal, 16S
PubMed: 35260689
DOI: 10.1038/s41598-022-07796-y -
Biochimica Et Biophysica Acta.... Jun 2023The objective of this study was to explore the role of ferroptosis in the formation of calcium oxalate (CaOx) kidney stones and the regulatory mechanism of the ankyrin...
The objective of this study was to explore the role of ferroptosis in the formation of calcium oxalate (CaOx) kidney stones and the regulatory mechanism of the ankyrin repeat domain 1 (ANKRD1) gene. The study found that the Nrf2/HO-1 and p53/SLC7A11 signaling pathways were activated in the kidney stone model group, and the expression of the ferroptosis marker proteins SLC7A11 and GPX4 was significantly reduced, while the expression of ACSL4 was significantly increased. The expression of the iron transport-related proteins CP and TF increased significantly, and Fe accumulated in the cell. The expression of HMGB1 increased significantly. In addition, the level of intracellular oxidative stress was increased. The gene with the most significant difference caused by CaOx crystals in HK-2 cells was ANKRD1. Silencing or overexpression of ANKRD1 by lentiviral infection technology regulated the expression of the p53/SLC7A11 signaling pathway, which regulated the ferroptosis induced by CaOx crystals. In conclusion, CaOx crystals can mediate ferroptosis through the Nrf2/HO-1 and p53/SLC7A11 pathways, thereby weakening the resistance of HK-2 cells to oxidative stress and other unfavorable factors, enhancing cell damage, and increasing crystal adhesion and CaOx crystal deposition in the kidney. ANKRD1 participates in the formation and development of CaOx kidney stones by activating ferroptosis mediated by the p53/SLC7A11 pathway.
Topics: Humans; Calcium Oxalate; Ferroptosis; NF-E2-Related Factor 2; Tumor Suppressor Protein p53; Kidney Calculi; Muscle Proteins; Nuclear Proteins; Repressor Proteins
PubMed: 36907445
DOI: 10.1016/j.bbamcr.2023.119452 -
Seminars in Nephrology Nov 2020Uric acid is an end product of purine metabolism in human beings. An unusual and still unexplained phenomenon is that higher primates have relatively high uric acid... (Review)
Review
Uric acid is an end product of purine metabolism in human beings. An unusual and still unexplained phenomenon is that higher primates have relatively high uric acid levels in body fluids owing to a combination of absence of degradation and renal retention. The physiologic purpose of high uric acid levels still is enigmatic, but the pathobiologic burden is a variety of crystallopathies owing to the low aqueous solubility of uric acid such as gouty arthritis and acute uric acid nephropathy. In the urinary space, three distinct conditions result from chronic uric acid and/or urate precipitation. The first and most common variety is uric acid urolithiasis. In this condition, urate is a victim of a systemic metabolic disease in which increased acid load to the kidney is coupled with diminished urinary buffer capacity owing to defective ammonium excretion, resulting in titration of urate to its sparingly soluble protonated counterpart, uric acid, and the formation of stones. Uric acid is the innocent bystander of the crime. The second variety is hyperuricosuric calcium urolithiasis, in which uric acid confers lithogenicity via promotion of calcium oxalate precipitation by multiple mechanisms involving soluble, colloidal, and crystalline urate salts. Uric acid is the instigator of the crime. The third and least common condition involves urate as an integral part of the urolith as an ammonium salt driven by high ammonium and high urate concentrations in urine. Here, uric acid is one of the perpetrators of the crime. Both known and postulated pathogenesis of these three types of urolithiasis are reviewed and summarized.
Topics: Animals; Calcium Oxalate; Humans; Kidney Diseases; Uric Acid; Urinary Calculi; Urolithiasis
PubMed: 33678311
DOI: 10.1016/j.semnephrol.2020.12.003 -
Revue Medicale de Liege Jul 2022Primary hyperoxaluria type 1 is a rare autosomal recessive disorder leading to oxalate overproduction by deficiency in the liver-specific enzyme alanine-glyoxylate...
Primary hyperoxaluria type 1 is a rare autosomal recessive disorder leading to oxalate overproduction by deficiency in the liver-specific enzyme alanine-glyoxylate transaminase (AGT). Oxalate is a poorly soluble molecule that binds calcium and deposits in the entire organism leading to oxalosis. Its elimination is mainly carried out by kidneys. Hence the first manifestations are frequently of urinary concern and whitout any early care, progression of the disease to end-stage renal failure cannot be avoided. The only etiological treatment has long been combined liver-kidney transplantation because it restaures enzymatic function and replaces pathological kidneys. However, for a few years now, numerous studies are carried out on this subject and promising results have already been published with a new drug, lumasiran. From a clinical case, we describe the different options for the therapeutic management of primary hyperoxaluria type 1.
Topics: Humans; Hyperoxaluria, Primary; Nephrocalcinosis; Oxalates; RNA, Small Interfering
PubMed: 35924494
DOI: No ID Found -
Viruses Aug 2022Soybean leaf-associated gemygorvirus-1 (SlaGemV-1) is a CRESS-DNA virus classified in the family Genomoviridae, which causes hypovirulence and abolishes sclerotia...
Soybean leaf-associated gemygorvirus-1 (SlaGemV-1) is a CRESS-DNA virus classified in the family Genomoviridae, which causes hypovirulence and abolishes sclerotia formation in infected fungal pathogens under the family Sclerotiniaceae. To investigate the mechanisms involved in the induction of hypovirulence, RNA-Seq was compared between virus-free and SlaGemV-1-infected strain DK3. Overall, 4639 genes were differentially expressed, with 50.5% up regulated and 49.5% down regulated genes. GO enrichments suggest changes in integral membrane components and transmission electron microscopy images reveal virus-like particles localized near the inner cell membrane. Differential gene expression analysis focused on genes responsible for cell cycle and DNA replication and repair pathways, ubiquitin proteolysis, gene silencing, methylation, pathogenesis-related, sclerotial development, carbohydrate metabolism, and oxalic acid biosynthesis. Carbohydrate metabolism showed the most changes, with two glycoside hydrolase genes being the most down regulated by -2396.1- and -648.6-fold. Genes relating to pathogenesis showed consistent down regulation with the greatest being SsNep1, SsSSVP1, and Endo2 showing, -4555-, -14.7-, and -12.3-fold changes. The cell cycle and DNA replication/repair pathways were almost entirely up regulated including a putative cyclin and separase being up regulated 8.3- and 5.2-fold. The oxalate decarboxylase genes necessary for oxalic acid catabolism and oxalic acid precursor biosynthesis genes and its metabolism show down regulations of -17.2- and -12.1-fold changes. Sclerotial formation genes also appear differentially regulated including a melanin biosynthesis gene 1 and a sclerotia formation gene 2 with fold changes of 3.8 and -2.9.
Topics: Ascomycota; Cyclins; Glycoside Hydrolases; Melanins; Oxalic Acid; Plant Diseases; Separase; Ubiquitins; Virulence; Viruses
PubMed: 36146699
DOI: 10.3390/v14091892 -
Nutrients Dec 2020Kidney stone disease is increasing in prevalence, and the most common stone composition is calcium oxalate. Dietary oxalate intake and endogenous production of oxalate... (Review)
Review
Kidney stone disease is increasing in prevalence, and the most common stone composition is calcium oxalate. Dietary oxalate intake and endogenous production of oxalate are important in the pathophysiology of calcium oxalate stone disease. The impact of dietary oxalate intake on urinary oxalate excretion and kidney stone disease risk has been assessed through large cohort studies as well as smaller studies with dietary control. Net gastrointestinal oxalate absorption influences urinary oxalate excretion. Oxalate-degrading bacteria in the gut microbiome, especially may mitigate stone risk through reducing net oxalate absorption. Ascorbic acid (vitamin C) is the main dietary precursor for endogenous production of oxalate with several other compounds playing a lesser role. Renal handling of oxalate and, potentially, renal synthesis of oxalate may contribute to stone formation. In this review, we discuss dietary oxalate and precursors of oxalate, their pertinent physiology in humans, and what is known about their role in kidney stone disease.
Topics: Bacteria; Calcium Oxalate; Diet; Gastrointestinal Microbiome; Humans; Kidney; Kidney Calculi; Nephrolithiasis; Oxalates; Oxalobacter formigenes; Urolithiasis
PubMed: 33379176
DOI: 10.3390/nu13010062