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Experimental animal model studies suggest that calcium oxalate (CaOx) crystal deposition in the kidneys is associated with the development of oxidative stress, epithelial injury and inflammation. There is increased production of inflammatory molecules including osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1) and various subunits of in...
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Metabolic syndrome (MS) individuals have a higher risk of developing chronic kidney disease through unclear pathogenic mechanisms. MS has been also related with higher nephrolithiasis prevalence. To establish the influence of MS on renal function, we designed a murine model of combined metabolic syndrome and hyperoxaluria. Four groups of male Sprag...
Citations
... In a Aprt knock-out mice and the 2,8-dihydroxyadenine-induced nephrolithiasis model, Tzortzaki et al. identified a decreased IMPT1 gene (an organic cation transporter), which was expressed in the kidney and contributed to impaired renal function [44]. Genetic hyperoxaluria models, such as MCP-1, may induce experimental CaOx crystalluria [45]. The knock-out of sulfate anion transporter-1 gene (Sat1; also known as Slc26a1) led to the dysfunction of oxalate transportation and hemostasis that resulted in hyperoxaluria and CaOx stone formation in mice [46]. ...
... The other lithogenic agent was 1.5% potassium oxalate, which was added in a chow diet [45]. ...
Animals have stone disease too. There are several animal models for the research of human stone disease. Rodents are the most frequently used for stone research, although they are not prone to forming crystals in the kidneys. Ethylene glycol (EG), sodium oxalate and l-hydroxyproline are common lithogenic agents. Dogs and pigs were also reported as a study animal for stone disease. However, the breeding costs and body size are too high. The most-used genetic study animal for stone disease was the mouse, but it was high-cost. Calcium oxalate (CaOx) crystals can also be light microscopically observed in the Malphigian tubules of Drosophila melanogaster, induced by adding EG to the food. Genetic studies of flies can be done by cross-breeding, and this has a lower cost than using mice. The fly model also has several advantages, including minimal breeding equipment, the fact that it is easier to reach larger numbers in a short time with flies, that crystals can be observed under microscopy, and that they allow genetic study. We suggest the fly will be an ideal animal model for stone research in the future.
... В экспериментальных исследованиях на мо дели уролитиаза у мышей продемонстриро вано отсутствие заметного влияния МСР 1 на задержку кристаллов оксалата кальция. По данным исследователей, почечная продук ция МСР 1 не увеличивается без отложения в почках кристаллов оксалатов кальция [24]. Предполагается, что избыточная экспрессия и повышенная продукция МСР 1 является следствием взаимодействия между эпители альными клетками и кристаллами оксалата кальция уже после их отложения в канальцах почки [19,33]. ...
The review presents the data on clinical diagnostic value of studying one of the components of urinary proteome - macrophage chemotactic protein -1 (MCP-1). Along with the general characteristics of MCP-1, there are given the data on changes in its concentration regarding various diseases of the urinary system. It was shown that for various diseases and research conditions, the concentration of MCP-1 can be an important diagnostic criterion in assessing inflammatory, metabolic, fibrotic and other renal lesions.
... Today, the leading role of intestinal microbiota in the support of the balanced status of T-regulatory cells /T-helper type 17 (Treg / Th17) has already been proven [10,13,14]. MCP-1 plays an important role in attracting monocytes and macrophages in the blood to any type of inflammatory tissues including the intestine and kidneys [15,16]. Until recently, it was thought that the main source of MCP-1 was epithelia at the site of inflammation. ...
... Until recently, it was thought that the main source of MCP-1 was epithelia at the site of inflammation. But, today, the experimental studies have proven the ability of MCP-1 production even by normal epithelial cells of the intestine and kidneys [16]. At the same time, overexpression of MCP-1 can also be the result of the interaction between renal epithelial cells and CaOx crystals after their sedimentation in the renal tubules [26]. ...
... At the same time, overexpression of MCP-1 can also be the result of the interaction between renal epithelial cells and CaOx crystals after their sedimentation in the renal tubules [26]. Thus, the overproduction of this chemokine in women with recurrent pyelonephritis can be explained by the oxalate-induced inflammatory reaction of the kidneys [16]. ...
The purpose of the study was to investigate the immune response in patients with recurrent pyelonephritis depending on the presence of hyperoxaluria.The observational cross-sectional study involved 64 women with recurrent pyelonephritis. The patients' immune response was evaluated by determination of serum concentrations of interleukins (IL)-4,-17,-18,-23, tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Depending on the presence of hyperoxaluria (urinary oxalate excretion was more than 0.45 mmol per day), the patients were allocated into 2 groups: the women with hyperoxaluria were included to group I (n = 35) and the patients with normal levels of oxalate excretion were included to group II (n = 29). The control group consisted of 25 practically healthy donors.The mean age in the patient population was 31.6 ± 7.7. The average number of pyelonephritis recurrence was 6.4 ± 1.9 per year. We identified a moderate direct correlation between the levels of the urinary oxalate excretion and the number of pyelonephritis recurrences per year (r = 0.71, p < 0.0001) and the inverse strong correlation between oxaluria and GFR level (r = 0.75, p < 0.0001). The patients with hyperoxaluria had increased synthesis of the blood concentration of TNF-α, MCP-1, IL-4,-17 and 23. Our results have provided preliminary evidence that hyperoxaluria is associated with increased serum levels of IL-4,-17,-23, MCP-1 and TNF-α. The larger-scale studies are needed for further confirmation of our findings.
... In a study by Masanori et al., adiposity in Otsuka Long-Evans Tokushima fatty rats elevated expressions of MCP-1 and OPN, mediated by ROS production, resulting in the increasing of CaOx crystal deposition in the kidney via accelerating the processes of crystal retention and the inflammatory [40]. As discussed, CaOx crystal deposition in the kidneys has a bearing on the development of oxidative stress, epithelial injury and inflammation [41]. We found that silencing MUC4 can regulating oxidative stress-related factors in RETC, reducing H 2 O 2 and MDA levels and increasing SOD, CAT and GSH-Px levels. ...
Background/aims:
Nephrolithiasis plagues a great number of patients all over the world. Increasing evidence shows that the extracellular signal-regulated kinase (ERK) signaling pathway and renal tubular epithelial cell (RTEC) dysfunction and attrition are central to the pathogenesis of kidney diseases. Mucin 4 (MUC4) is reported as an activator of ERK signaling pathway in epithelial cells. In this study, using rat models of calcium oxalate (CaOx) nephrolithiasis, the present study aims to define the roles of MUC4 and ERK signaling pathway as contributors to oxidative stress and CaOx crystal formation in RTEC.
Methods:
Data sets of nephrolithiasis were searched using GEO database and a heat flow map was drawn. Then MUC4 function was predicted. Wistar rats were prepared for the purpose of model establishment of ethylene glycol and ammonium chloride induced CaOx nephrolithiasis. In order to assess the detailed regulatory mechanism of MUC4 silencing on the ERK signaling pathway and RTEC, we used recombinant plasmid to downregulate MUC4 expression in Wistar rat-based models. Samples from rat urine, serum and kidney tissues were reviewed to identify oxalic acid and calcium contents, BUN, Cr, Ca2+ and P3+ levels, calcium crystal formation in renal tubules and MUC4 positive expression rate. Finally, RT-qPCR, Western blot analysis, and ELISA were employed to access oxidative stress state and CaOx crystal formation in RTEC.
Results:
Initially, MUC4 was found to have an influence on the process of nephrolithiasis. MUC4 was upregulated in the CaOx nephrolithiasis model rats. We proved that the silencing of MUC4 triggered the inactivation of ERK signaling pathway. Following the silencing of MUC4 or the inhibition of ERK signaling pathway, the oxalic acid and calcium contents in rat urine, BUN, Cr, Ca2+ and P3+ levels in rat serum, p-ERK1/2, MCP-1 and OPN expressions in RTEC and H2O2 and MDA levels in the cultured supernatant were downregulated, but the GSH-Px, CAT and SOD levels in the cultured supernatant were increased. Moreover, MUC4 silencing or ERK signaling pathway inactivation may decrease the formation of CaOx crystals.
Conclusion:
Taken together, silencing of MUC4 can inactivate the ERK signaling pathway and further restrain oxidative stress and CaOx crystal formation in RTEC. Thus, MUC4 represents a potential investigative focus target in nephrolithiasis.
... 17,18 Mouse models with induced hyperoxaluria but without observable stones have shown normal CCL-2 and osteopontin levels, suggesting that elevated papillary tip and urinary levels of oxalate do not trigger inflammatory reactions, and crystal deposition is likely required to activate monocytes. 19 In a study of lithogenic mice, which produce stones when administered glyoxylate, deposition of calcium oxalate into the renal interstitium was found to peak by day 9 of exposure, and almost completely resolved by day 16. Accompanying the rise and fall of crystal deposition was a sharp increase in the number of monocytes and associated cytokines. ...
... Accompanying the rise and fall of crystal deposition was a sharp increase in the number of monocytes and associated cytokines. Cells were seen to be phagocytosing crystals, 19 findings also noted in cultured macrophage studies. 20 Oxidative stress has been displayed in cultured mouse epithelial cells exposed to apatite crystals, with maximal response found once crystals were on the basal side of the basement membrane. ...
Introduction:
Intrarenal inflammation has been implicated in the pathogenesis of nephrolithiasis, with prior work showing increased urine levels of IL-6, IL-8, and CCL-2 in stone patients. However, no studies have assessed for inflammation in the renal papillae. We sought to characterize novel papillary tip and urinary biomarkers in stone patients.
Methods:
92 patients with nephrolithiasis undergoing percutaneous nephrolithotomy were enrolled. Papillary tip biopsies, kidney urine, and bladder urine were collected, as well as voided urine from 8 healthy volunteers. QT-PCR was performed to measure inflammatory gene expression.
Results:
84-gene PCR array revealed significant elevation of several cytokines in stone patients vs controls (fold change 2.3 - 694). 24 genes were selected for final analysis. In 41 pairs of urine samples, levels of CCL5, CD40, FasL, RIPK2, SELE, TLR3, and IL-15 were significantly elevated in kidney vs bladder urine (p0.0001 - 0.04). In 23 triplets of samples, expression of these cytokines plus CCL2, CCL7, CCR2, CSF1, CXCL9, and CXCL10 were significantly greater in papillary tips versus urine samples (p0.001 - 0.05). Cytokine elevation was independent of maximum post-operative heart rate, respiratory rate, temperature, leukocyte count, history of UTI in the past year, presence or absence of antibiotics at the time of surgery, and stone composition (all p>0.05) Conclusion: Expression of CCL-2, CCL-5, CCL-7, CCR-2, CD40, CSF1, CXCL-9, CXCL-10, Fas-L, RIPK2, SELE, and TLR-3, is markedly elevated in the papillary tips, kidney urine, and bladder urine of nephrolithiasis patients. Cytokine elevation was independent of signs of systemic inflammation. These findings further support the role of inflammation in nephrolithiasis, and imply that the inflammatory process likely begins at the renal papillae. These may represent novel biomarkers of stone disease which may be useful in basic nephrolithiasis research, disease diagnosis, and prognosis.
... Hyperoxaluria and CaOx crystal deposition in the kidneys are also associated with significant changes in the production of macromolecules that modulate crystal aggregation and crystal adherence to the renal epithelium [31,34,[40][41][42][43][44][45][46][47][48][49][50][51]. ...
Crystallization by itself is not harmful as long as the crystals are not retained in the kidneys and are allowed to pass freely down the renal tubules to be excreted in the urine. A number of theories have been proposed, and studies performed, to determine the mechanisms involved in crystal retention within the kidneys. It has been suggested that urinary transit through the nephron is too fast for crystals to grow large enough to be retained. Thus, free particle mechanism alone cannot lead to stone formation, and there must be a mechanism for crystal fixation within the kidneys. Animal model studies suggest that crystal retention is possible through both the free- and fixed-particle mechanisms. Crystal–cell interaction leads to pathological changes which promote crystal attachment to either epithelial cells or their basement membrane. Alternatively, crystals aggregate and produce large enough particles to block the tubules particularly at sites, where urinary flow is affected because of changes in the luminal diameter of the tubule. Crystal deposits plugging the openings of the ducts of Bellini may be the result of such a phenomenon. Intratubular crystals translocating to renal interstitium may produce osteogenic changes in the epithelial or endothelial cells resulting in the formation of the Randall’s plaques. Thus, fixation appears to be either through the formation of Randall’s plugs, crystal plugs clogging the openings of the ducts of Bellini or sub-epithelial crystal deposits, and the Randall’s plaques.
