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PloS One 2022Kidney stone is one of the most frequent urinary tract diseases, affecting 10% of the population and displaying a high recurrence rate. Kidney stones are the result of...
Kidney stone is one of the most frequent urinary tract diseases, affecting 10% of the population and displaying a high recurrence rate. Kidney stones are the result of salt supersaturation, including calcium and oxalate. We have previously identified Esophageal cancer-related gene 4 (Ecrg4) as being modulated by hypercalciuria. Ecrg4 was initially described as a tumor suppressor gene in the esophagus. Lately, it was shown to be involved as well in apoptosis, cell senescence, cell migration, inflammation and cell responsiveness to chemotherapy. To the best of our knowledge, nothing is known about ECRG4's function in the renal tissue and its relationship with calciuria. We hypothesized that the increased expression of Ecrg4 mRNA is triggered by hypercalciuria and might modulate intratubular calcium-oxalate precipitation. In this study, we have first (i) validated the increased Ecrg4 mRNA in several types of hypercalciuric mouse models, then (ii) described the Ecrg4 mRNA expression along the nephron and (iii) assessed ECRG4's putative role in calcium oxalate nephropathy. For this, Ecrg4 KO mice were challenged with a kidney stone-inducing diet, rich in calcium and oxalate precursor. Taken together, our study demonstrates that Ecrg4's expression is restricted mainly to the distal part of the nephron and that the Ecrg4 KO mice develop less signs of tubular obstruction and less calcium-oxalate deposits. This promotes Ecrg4 as a modulator of renal crystallization and may open the way to new therapeutic possibilities against calcium oxalate nephropathy.
Topics: Animals; Calcium; Calcium Oxalate; Calcium, Dietary; Esophageal Neoplasms; Hypercalciuria; Kidney Calculi; Mice; RNA, Messenger; Renal Insufficiency
PubMed: 36227903
DOI: 10.1371/journal.pone.0275972 -
International Journal of Molecular... May 2021Polyoxalate (POx) and copolyoxalate (CPOx) smart polymers are topics of interest the field of inflammation. This is due to their drug delivery ability and their... (Review)
Review
Polyoxalate (POx) and copolyoxalate (CPOx) smart polymers are topics of interest the field of inflammation. This is due to their drug delivery ability and their potential to target reactive oxygen species (ROS) and to accommodate small molecules such as curcumin, vanilline, and p-Hydroxybenzyl alcohol. Their biocompatibility, ultra-size tunable characteristics and bioimaging features are remarkable. In this review we discuss the genesis and concept of oxylate smart polymer-based particles and a few innovative systemic delivery methods that is designed to counteract the inflammation and other aging-associated diseases (AADs). First, we introduce the ROS and its role in human physiology. Second, we discuss the polymers and methods of incorporating small molecule in oxalate backbone and its drug delivery application. Finally, we revealed some novel proof of concepts which were proven effective in disease models and discussed the challenges of oxylate polymers.
Topics: Aging; Drug Delivery Systems; Humans; Oxalates; Stimuli Responsive Polymers
PubMed: 34070585
DOI: 10.3390/ijms22115607 -
Molecules (Basel, Switzerland) Apr 2023Oxalate is a divalent organic anion that affects many biological and commercial processes. It is derived from plant sources, such as spinach, rhubarb, tea, cacao, nuts,... (Review)
Review
Oxalate is a divalent organic anion that affects many biological and commercial processes. It is derived from plant sources, such as spinach, rhubarb, tea, cacao, nuts, and beans, and therefore is commonly found in raw or processed food products. Oxalate can also be made endogenously by humans and other mammals as a byproduct of hepatic enzymatic reactions. It is theorized that plants use oxalate to store calcium and protect against herbivory. Clinically, oxalate is best known to be a major component of kidney stones, which commonly contain calcium oxalate crystals. Oxalate can induce an inflammatory response that decreases the immune system's ability to remove renal crystals. When formulated with platinum as oxaliplatin (an anticancer drug), oxalate has been proposed to cause neurotoxicity and nerve pain. There are many sectors of industry that are hampered by oxalate, and others that depend on it. For example, calcium oxalate is troublesome in the pulp industry and the alumina industry as it deposits on machinery. On the other hand, oxalate is a common active component of rust removal and cleaning products. Due to its ubiquity, there is interest in developing efficient methods to quantify oxalate. Over the past four decades, many diverse methods have been reported. These approaches include electrochemical detection, liquid chromatography or gas chromatography coupled with mass spectrometry, enzymatic degradation of oxalate with oxalate oxidase and detection of hydrogen peroxide produced, and indicator displacement-based methods employing fluorescent or UV light-absorbing compounds. Enhancements in sensitivity have been reported for both electrochemical and mass-spectrometry-based methods as recently as this year. Indicator-based methods have realized a surge in interest that continues to date. The diversity of these approaches, in terms of instrumentation, sample preparation, and sensitivity, has made it clear that no single method will work best for every purpose. This review describes the strengths and limitations of each method, and may serve as a reference for investigators to decide which approach is most suitable for their work.
Topics: Humans; Animals; Oxalates; Calcium Oxalate; Gas Chromatography-Mass Spectrometry; Kidney; Kidney Calculi; Mammals
PubMed: 37049969
DOI: 10.3390/molecules28073206 -
Urolithiasis Dec 2020Measurement of oxalate in the blood is essential for monitoring primary hyperoxaluria patients with progressive renal impairment and on dialysis prior to... (Comparative Study)
Comparative Study
Measurement of oxalate in the blood is essential for monitoring primary hyperoxaluria patients with progressive renal impairment and on dialysis prior to transplantation. As no external quality assurance scheme is available for this analyte, we conducted a sample exchange scheme between six laboratories specifically involved with the investigation of primary hyperoxaluria to compare results. The methodologies compared were gas chromatography/mass spectrometry (GCMS), ion chromatography with mass spectrometry (ICMS), and enzymatic methods using oxalate oxidase and spectrophotometry. Although individual laboratories performed well in terms of reproducibility and linearity, there was poor agreement (absolute values) between centres as illustrated by a longer-term comparison of patient results from two of the participating laboratories. This situation was only partly related to differences in calibration and mainly reflected the lower recoveries seen with the ultrafiltration of samples. These findings lead us to conclude that longitudinal monitoring of primary hyperoxaluria patients with deteriorating kidney function should be performed by a single consistent laboratory and the methodology used should always be defined. In addition, plasma oxalate concentrations reported in registry studies and those associated with the risk of systemic oxalosis in published studies need to be interpreted in light of the methodology used. A reference method and external quality assurance scheme for plasma oxalate analysis would be beneficial.
Topics: Hematologic Tests; Humans; Hyperoxaluria, Primary; Oxalates
PubMed: 32472220
DOI: 10.1007/s00240-020-01197-4 -
The Veterinary Record Aug 2021The features of juvenile-onset calcium oxalate urolithiasis in dogs have not been previously reported.
BACKGROUND
The features of juvenile-onset calcium oxalate urolithiasis in dogs have not been previously reported.
METHODS
Calcium oxalate urolith submissions to the Minnesota Urolith Center between 2012 and 2016 were analyzed to identify those originating from juvenile (≤2 years, n = 510) or mature (7-9 years, n = 39,093) dogs. Breed, sex, urolith salt type and urolith location were compared between groups. Breeds represented in both groups were also compared with respect to sex, urolith salt type and urolith location.
RESULTS
French (odds ratios [OR] = 14.7, p < 0.001) and English (OR = 14.3, p < 0.001) Bulldogs were overrepresented in juvenile submissions. All juvenile French and English Bulldogs were male. Across all breeds, juvenile dogs were more likely to be male (89%, p < 0.001) than mature dogs (79%). Juvenile dogs were also more likely to form dihydrate stones compared to mature dogs (33% versus 14%, respectively; p < 0.001). Breed differences were discovered in sex, urolith salt type and stone location.
CONCLUSIONS
French and English Bulldogs comprise a greater proportion of juvenile calcium oxalate urolith submissions than expected based on their rarity in mature submissions. Inherited risk factors, particularly X chromosome variants, should be investigated due to the strong breed and sex predispositions identified.
Topics: Age of Onset; Animals; Calcium Oxalate; Dog Diseases; Dogs; Female; Male; Risk Factors; Urolithiasis
PubMed: 34357620
DOI: 10.1002/vetr.141 -
Current Opinion in Insect Science Oct 2021The insect renal (Malpighian) tubules are functionally homologous to the mammalian kidney. Accumulating evidence indicates that renal tubule crystals form in a manner... (Review)
Review
The insect renal (Malpighian) tubules are functionally homologous to the mammalian kidney. Accumulating evidence indicates that renal tubule crystals form in a manner similar to mammalian kidney stones. In Drosophila melanogaster, crystals can be induced by diet, toxic substances, or genetic mutations that reflect circumstances influencing or eliciting kidney stones in mammals. Incredibly, many mammalian proteins have distinct homologs in Drosophila, and the function of most homologs have been demonstrated to recapitulate their mammalian and human counterparts. Here, we discuss the present literature establishing Drosophila as a nephrolithiasis model. This insect model may be used to investigate and understand the etiology of kidney stone diseases, especially with regard to calcium oxalate, calcium phosphate and xanthine or urate crystallization.
Topics: Animals; Calcium Oxalate; Disease Models, Animal; Drosophila melanogaster; Malpighian Tubules; Nephrolithiasis
PubMed: 34044181
DOI: 10.1016/j.cois.2021.05.003 -
Journal of Nanobiotechnology Dec 2022Oxidative stress damage to renal epithelial cells is the main pathological factor of calcium oxalate calculi formation. The development of medicine that could alleviate...
Oxidative stress damage to renal epithelial cells is the main pathological factor of calcium oxalate calculi formation. The development of medicine that could alleviate oxidative damage has become the key to the prevention and treatment of urolithiasis. Herein, porous nanorods CeO nanoparticles (CNPs) were selected from CeO with different morphologies as an antioxidant reagent to suppress kidney calcium oxalate crystal depositions with excellent oxidation resistance due to its larger specific surface area. The reversible transformation from Ce to Ce could catalyze the decomposition of excess free radicals and act as a biological antioxidant enzyme basing on its strong ability to scavenge free radicals. The protection capability of CNP against oxalate-induced damage and the effect of CNP on calcium oxalate crystallization were studied. CNP could effectively reduce reactive oxygen species production, restore mitochondrial membrane potential polarity, recover cell cycle progression, reduce cell death, and inhibit the formation of calcium oxalate crystals on the cell surface in vitro. The results of high-throughput sequencing of mRNA showed that CNPs could protect renal epithelial cells from oxidative stress damage caused by high oxalate by suppressing the expression gene of cell surface adhesion proteins. In addition, CNP can significantly reduce the pathological damage of renal tubules and inhibit the deposition of calcium oxalate crystals in rat kidneys while having no significant side effect on other organs and physiological indicators in vivo. Our results provide a new strategy for CNP as a potential for clinical prevention of crystalline kidney injury and crystal deposition.
Topics: Calcium Oxalate; Kidney; Oxidative Stress; Free Radicals
PubMed: 36482378
DOI: 10.1186/s12951-022-01726-w -
Pflugers Archiv : European Journal of... Feb 2023Elevated levels of the intracellular second messenger cAMP can stimulate intestinal oxalate secretion however the membrane transporters responsible are unclear. Oxalate...
Elevated levels of the intracellular second messenger cAMP can stimulate intestinal oxalate secretion however the membrane transporters responsible are unclear. Oxalate transport by the chloride/bicarbonate (Cl/HCO) exchanger Slc26a6 or PAT-1 (Putative Anion Transporter 1), is regulated via cAMP when expressed in Xenopus oocytes and cultured cells but whether this translates to the native epithelia is unknown. This study investigated the regulation of oxalate transport by the mouse intestine focusing on transport at the apical membrane hypothesizing PAT-1 is the target of a cAMP-dependent signaling pathway. Adopting the Ussing chamber technique we measured unidirectional C-oxalate and Cl flux ([Formula: see text] and [Formula: see text]) across distal ileum, cecum and distal colon, employing forskolin (FSK) and 3-isobutyl-1-methylxanthine (IBMX) to trigger cAMP production. FSK/IBMX initiated a robust secretory response by all segments but the stimulation of net oxalate secretion was confined to the cecum only involving activation of [Formula: see text] and distinct from net Cl secretion produced by inhibiting [Formula: see text]. Using the PAT-1 knockout (KO) mouse we determined cAMP-stimulated [Formula: see text] was not directly dependent on PAT-1, but it was sensitive to mucosal DIDS (4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid), although unlikely to be another Cl/HCO exchanger given the lack of trans-stimulation or cis-inhibition by luminal Cl or HCO. The cAMP-activated oxalate efflux was reliant on CFTR (Cystic Fibrosis Transmembrane conductance Regulator) activity, but only in the presence of PAT-1, leading to speculation on the involvement of a multi-transporter regulatory complex. Further investigations at the cellular and molecular level are necessary to define the mechanism and transporter(s) responsible.
Topics: Animals; Mice; 1-Methyl-3-isobutylxanthine; Ion Transport; Biological Transport; Membrane Transport Proteins; Cecum; Chlorides; Oxalates; Cystic Fibrosis Transmembrane Conductance Regulator; Bicarbonates; Sulfate Transporters; Antiporters
PubMed: 36044064
DOI: 10.1007/s00424-022-02742-3 -
Biochimica Et Biophysica Acta.... Jan 2021The Primary Hyperoxalurias (PH) are rare disorders of metabolism leading to excessive endogenous synthesis of oxalate and recurring calcium oxalate kidney stones....
The Primary Hyperoxalurias (PH) are rare disorders of metabolism leading to excessive endogenous synthesis of oxalate and recurring calcium oxalate kidney stones. Alanine glyoxylate aminotransferase (AGT), deficient in PH type 1, is a key enzyme in limiting glyoxylate oxidation to oxalate. The affinity of AGT for its co-substrate, alanine, is low suggesting that its metabolic activity could be sub-optimal in vivo. To test this hypothesis, we examined the effect of L-alanine supplementation on oxalate synthesis in cell culture and in mouse models of Primary Hyperoxaluria Type 1 (Agxt KO), Type 2 (Grhpr KO) and in wild-type mice. Our results demonstrated that increasing L-alanine in cells decreased synthesis of oxalate and increased viability of cells expressing GO and AGT when incubated with glycolate. In both wild type and Grhpr KO male and female mice, supplementation with 10% dietary L-alanine significantly decreased urinary oxalate excretion ~30% compared to baseline levels. This study demonstrates that increasing the availability of L-alanine can increase the metabolic efficiency of AGT and reduce oxalate synthesis.
Topics: Alanine; Alcohol Oxidoreductases; Animals; CHO Cells; Cricetulus; Hyperoxaluria, Primary; Mice; Mice, Knockout; Oxalates; Transaminases
PubMed: 33002578
DOI: 10.1016/j.bbadis.2020.165981 -
Cellular and Molecular Life Sciences :... Sep 2023Surgical crushing of stones alone has not addressed the increasing prevalence of kidney stones. A promising strategy is to tackle the kidney damage and crystal...
FKBP5 deficiency attenuates calcium oxalate kidney stone formation by suppressing cell-crystal adhesion, apoptosis and macrophage M1 polarization via inhibition of NF-κB signaling.
Surgical crushing of stones alone has not addressed the increasing prevalence of kidney stones. A promising strategy is to tackle the kidney damage and crystal aggregation inherent in kidney stones with the appropriate therapeutic target. FKBP prolyl isomerase 5 (FKBP5) is a potential predictor of kidney injury, but its status in calcium oxalate (CaOx) kidney stones is not clear. This study attempted to elucidate the role and mechanism of FKBP5 in CaOx kidney stones. Lentivirus and adeno-associated virus were used to control FKBP5 expression in a CaOx kidney stone model. Transcriptomic sequencing and immunological assays were used to analyze the mechanism of FKBP5 deficiency in CaOx kidney stones. The results showed that FKBP5 deficiency reduced renal tubular epithelial cells (RTEC) apoptosis and promoted cell proliferation by downregulating BOK expression. It also attenuated cell-crystal adhesion by downregulating the expression of CDH4. In addition, it inhibited M1 polarization and chemotaxis of macrophages by suppressing CXCL10 expression in RTEC. Moreover, the above therapeutic effects were exerted by inhibiting the activation of NF-κB signaling. Finally, in vivo experiments showed that FKBP5 deficiency attenuated stone aggregation and kidney injury in mice. In conclusion, this study reveals that FKBP5 deficiency attenuates cell-crystal adhesion, reduces apoptosis, promotes cell proliferation, and inhibits macrophage M1 polarization and chemotaxis by inhibiting NF-κB signaling. This provides a potential therapeutic target for CaOx kidney stones.
Topics: Animals; Mice; NF-kappa B; Calcium Oxalate; Signal Transduction; Kidney Calculi; Apoptosis
PubMed: 37740796
DOI: 10.1007/s00018-023-04958-7