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Hyperoxaluria‐induced calcium oxalate (CaOx) deposition is the key factor in kidney stone formation, for which adipose‐derived stromal cells (ADSCs) have been used as a therapeutic treatment. Studies revealed that miR‐20b‐3p is down‐regulated in hypercalciuric stone‐forming rat kidney. To investigate whether ADSC‐derived miR‐20b‐3p‐enriched exosomes protect against kidney stones, an ethylene glycol (EG)‐induced hyperoxaluria rat model and an in vitro model of oxalate‐induced NRK‐52E cells were established to explore the protective mechanism of miR‐20b‐3p. The results showed that miR‐20b‐3p levels were decreased following hyperoxaluria in the urine of patients and in kidney tissues from animal models. Furthermore, treatment with miR‐20b‐3p‐enriched exosomes from ADSCs protected EG‐induced hyperoxaluria rats, and cell experiments confirmed that co‐culture with miR‐20b‐3p‐enriched exosomes alleviated oxalate‐induced cell autophagy and the inflammatory response by inhibiting ATG7 and TLR4. In conclusion, ADSC‐derived miR‐20b‐3p‐enriched exosomes protected against kidney stones by suppressing autophagy and inflammatory responses.

Background Calcium oxalate (CaOx) nephrolithiasis, a highly prevalent renal disorder, underscores an urgent demand for novel therapeutic strategies to prevent stone formation. Accumulating evidence has elucidated a robust link between renal CaOx stone formation and gut microbiota dysbiosis, suggesting microbial modulation as a potential therapeutic target. Recently, microbiome-targeted interventions, particularly synbiotic formulations, have demonstrated promising therapeutic efficacy in mitigating hyperoxaluria and preventing renal stone formation. Results We developed a novel synbiotic formulation containing Lactiplantibacillus plantarum , Lacticaseibacillus casei , Bifidobacterium breve , and prebiotic galactooligosaccharides (GOS). Subsequently, the synbiotic or its individual components (multi-strain probiotic mixture or GOS) were administered to ethylene glycol (EG)-induced hyperoxaluric rats via daily oral gavage for 28 days. We found that the synbiotic formulation exhibited superior anti-nephrolithic activity compared to the multi-strain probiotic mixture or GOS alone, attributable to the synergistic effects of probiotic-prebiotic combinations. Remarkably, synbiotic supplementation not only significantly reversed the EG-induced reductions in gut microbiota richness and evenness, but also restored the microbiota architecture. Additionally, a significant increase was observed in the relative abundance of multiple beneficial genera implicated in short-chain fatty acids (SCFAs) production, including Prevotellaceae_Ga6A1_group , UCG_009 , Candidatus_Saccharimonas , Prevotellaceae_UCG_001 and Phascolarctobacterium . Furthermore, synbiotic supplementation reduced systemic oxalate overload by alleviating intestinal barrier damage and modulating mucosal oxalate transporter expression. Conclusion Our findings demonstrate that synbiotic intervention effectively reverses EG-induced hyperoxaluria by reversing gut microbiota dysbiosis to modulate oxalate homeostasis. Thus, this study not only proposes a synbiotic formulation for nephrolithiasis prevention but also elucidates its mechanistic basis, offering potential therapeutic advancements in disease management.

This study was aimed to investigate the preventive effects of N-acetyl-l-cysteine (NAC) against renal tubular cell injury induced by oxalate and stone formation and further explore the related mechanism. Transcriptome sequencing combined with bioinformatics analysis were performed to identify differentially expressed gene (DEG) and related pathways. HK-2 cells were pretreated with or without antioxidant NAC/with or silencing DEG before exposed to sodium oxalate. Then, the cell viability, oxidative biomarkers of superoxidase dismutase (SOD) and malondialdehyde (MDA), apoptosis and cell cycle were measured through CCK8, ELISA and flow cytometry assay, respectively. Male SD rats were separated into control group, hyperoxaluria (HOx) group, NAC intervention group, and TGF-β/SMAD pathway inhibitor group. After treatment, the structure changes and oxidative stress and CaOx crystals deposition were evaluated in renal tissues by H&E staining, immunohistochemical and Pizzolato method. The expression of TGF-β/SMAD pathway related proteins (TGF-β1, SMAD3 and SMAD7) were determined by Western blot in vivo and in vitro. CDKN2B is a DEG screened by transcriptome sequencing combined with bioinformatics analysis, and verified by qRT-PCR. Sodium oxalate induced declined HK-2 cell viability, in parallel with inhibited cellular oxidative stress and apoptosis. The changes induced by oxalate in HK-2 cells were significantly reversed by NAC treatment or the silencing of CDKN2B. The cell structure damage and CaOx crystals deposition were observed in kidney tissues of HOx group. Meanwhile, the expression levels of SOD and 8-OHdG were detected in kidney tissues of HOx group. The changes induced by oxalate in kidney tissues were significantly reversed by NAC treatment. Besides, expression of SMAD7 was significantly down-regulated, while TGF-β1 and SMAD3 were accumulated induced by oxalate in vitro and in vivo. The expression levels of TGF-β/SMAD pathway related proteins induced by oxalate were reversed by NAC. In conclusion, we found that NAC could play an anti-calculus role by mediating CDKN2B/TGF-β/SMAD axis.

Vanillin, a natural compound derived from vanilla beans, exhibits antioxidant and anti-inflammatory properties, which may contribute to the prevention and treatment of renal stones. Therefore, this study is aimed to investigate the potential antiurolithic effect of vanillin in male hyperoxaluric Wistar rats. Computational molecular docking studies were used to investigate the interaction process and verify vanillin’s role in the prevention of kidney stones containing calcium oxalate. Software tools were utilized to analyze the drug ligands’ additional molecular characteristics, absorption, distribution, metabolism, and excretion (ADME), and toxicity. Urinary crystals were induced in rats by adding 0.75% ethylene glycol (EG) in drinking water for 3 weeks, along with 1% ammonium chloride (AC) during the initial three days. Molecular docking analysis revealed strong binding interactions of vanillin with Human CTP: Phosphoethanolamine Cytidylyltransferase (PDB ID: 3ELB) at the C5P binding site, with a binding affinity of -7.6 kcal/mol, suggesting a potential molecular basis for its antiurolithic activity. In vivo study showed that vanillin treatment dose dependently (30, 100 and 300 mg/kg body weight) reduced hyperoxaluria, hypercalciuria and crystal counts in kidneys of hyperoxaluric rats. The current results of our study suggest that vanillin possesses potential antiurolithic activity, showing enhanced therapeutic effects in urolithiasis, which could be a safe, effective and non-invasive option in modern medicine for the management of urinary stones.

Background Calcium oxalate (CaOx) is the major constituent of about 75% of all urinary stone and the secondary hyperoxaluria is a primary risk factor. Current treatment options for the patients with hyperoxaluria and CaOx stone diseases are limited. Oxalate degrading bacteria might have beneficial effects on urinary oxalate excretion resulting from decreased intestinal oxalate concentration and absorption. Thus, the aim of the present study is to examine the in vivo oxalate degrading ability of genetically engineered Lactobacillus plantarum ( L. plantarum ) that constitutively expressing and secreting heterologous oxalate decarboxylase (OxdC) for prevention of CaOx stone formation in rats. The recombinants strain of L. plantarum that constitutively secreting (WCFS1OxdC) and non-secreting (NC8OxdC) OxdC has been developed by using expression vector pSIP401. The in vivo oxalate degradation ability for this recombinants strain was carried out in a male wistar albino rats. The group I control; groups II, III, IV and V rats were fed with 5% potassium oxalate diet and 14 th day onwards group II, III, IV and V were received esophageal gavage of L. plantarum WCFS1, WCFS1OxdC and NC8OxdC respectively for 2-week period. The urinary and serum biochemistry and histopathology of the kidney were carried out. The experimental data were analyzed using one-way ANOVA followed by Duncan’s multiple-range test. Results Recombinants L. plantarum constitutively express and secretes the functional OxdC and could degrade the oxalate up to 70–77% under in vitro . The recombinant bacterial treated rats in groups IV and V showed significant reduction of urinary oxalate, calcium, uric acid, creatinine and serum uric acid, BUN/creatinine ratio compared to group II and III rats ( P < 0.05). Oxalate levels in kidney homogenate of groups IV and V were showed significant reduction than group II and III rats ( P < 0.05). Microscopic observations revealed a high score (4+) of CaOx crystal in kidneys of groups II and III, whereas no crystal in group IV and a lower score (1+) in group V. Conclusion The present results indicate that artificial colonization of recombinant strain, WCFS1OxdC and NC8OxdC, capable of reduce urinary oxalate excretion and CaOx crystal deposition by increased intestinal oxalate degradation.

Enhanced sodium excretion is associated with intrarenal oxidative stress. The present study evaluated whether oxidative stress caused by high sodium (HS) may be involved in calcium oxalate crystal formation. Male rats were fed a sodium-depleted diet. Normal-sodium and HS diets were achieved by providing drinking water containing 0.3% and 3% NaCl, respectively. Rats were fed a sodium-depleted diet with 5% hydroxyl-L-proline (HP) for 7 and 42 days to induce hyperoxaluria and/or calcium oxalate deposition. Compared to normal sodium, HS slightly increased calcium excretion despite diuresis; however, the result did not reach statistical significance. HS did not affect the hyperoxaluria, hypocalciuria or supersaturation caused by HP; however, it increased calcium oxalate crystal deposition soon after 7 days of co-treatment. Massive calcium oxalate formation and calcium crystal excretion in HS+HP rats were seen after 42 days of treatment. HP-mediated hypocitraturia was further exacerbated by HS. Moreover, HS aggravated HP-induced renal injury and tubular damage via increased apoptosis and oxidative stress. Increased urinary malondialdehyde excretion, in situ superoxide production, NAD(P)H oxidase and xanthine oxidase expression and activity, and decreased antioxidant enzyme expression or activity in the HS+HP kidney indicated exaggerated oxidative stress. Interestingly, this redox imbalance was associated with reduced renal osteopontin and Tamm-Horsfall protein expression (via increased excretion) and sodium-dependent dicarboxylate cotransporter NaDC-1 upregulation. Collectively, our results demonstrate that a HS diet induces massive crystal formation in the hyperoxaluric kidney; this is not due to increased urinary calcium excretion but is related to oxidative injury and loss of anticrystallization defense.

A number of animal models have been developed to investigate calcium oxalate (CaOx) nephrolithiasis. Ethylene glycol (EG)-induced hyperoxaluria in rats is most common, but is criticized because EG and some of its metabolites are nephrotoxic and EG causes metabolic acidosis. Both oxalate (Ox) and CaOx crystals are also injurious to renal epithelial cells. Thus, it is difficult to distinguish the effects of EG and its metabolites from those induced by Ox and CaOx crystals. This study was performed to investigate hydroxy-L-proline (HLP), a common ingredient of many diets, as a hyperoxaluria-inducing agent. In rats, HLP has been shown to induce CaOx nephrolithiasis in only hypercalciuric conditions. Five percent HLP mixed with chow was given to male Sprague–Dawley rats for 63 days, resulting in hyperoxaluria, CaOx crystalluria, and nephrolithiasis. Crystal deposits were surrounded by ED-1-positive inflammatory cells. Cell injury and death was followed by regeneration, as suggested by an increase in proliferating cell nuclear antigen-positive cells. Both osteopontin (OPN) and CD44 were upregulated. Staining for CD44 and OPN was intense in cells lining the tubules that contained crystals. Along with a rise in urinary Ox and lactate dehydrogenase, there were significant increases in 8-isoprostane and hydrogen peroxide excretion, indicating that the oxidative stress induced cell injury. Thus, HLP-induced hyperoxaluria alone can induce CaOx nephrolithiasis in rats.

Hyperoxaluria2 may be primary or secondary. Primary hyperoxaluria results from an inherited defect in oxalate metabolism that results in increased endogenous production of oxalate (Box 2).2,3 Secondary hyperoxaluria may result from either dietary excess, enteric hyperabsorption (Figure 2), or enhanced endogeneous production resulting from exposure to its precursors (ascorbic acid) or from pyridoxine deficiency. The absorption of oxalate in the gastrointestinal tract is influenced by many factors, including gut health and function,4 oxalate intake or oxalate content of food5 (Appendix 2, available at www.cmaj.ca/lookup/suppl/ doi:10.1503/cmaj.151327/-/DC1) and, most importantly, the intake of other nutrients such as calcium, magnesium and fat.1 High levels of dietary calcium6 and magnesium7 inhibit oxalate absorption through formation of insoluble oxalate salts in the gastrointestinal tract that are poorly absorbed. In addition, food preparation can affect oxalate absorption, as seen with \"juicing.\"8 Juices are concentrated forms of fruits and vegetables that may have high amounts of oxalate. Consequently, the increased amount of fluid load in the juices can promote paracellular absorption of oxalate in the intestines.8 The bioavailability of the oxalate in the meal is more important than its amount. The oxalate content of cashews is moderate9 compared with other nuts; however, by consuming large amounts daily, the patient increased her total daily intake of oxalate to a level much higher than average (Box 1).10 In addition, her lower calcium intake promoted hyperabsorption of oxalate, because calcium was not available to bind oxalate in the gut. Furthermore, the higher fat content of cashews (about 45°%), although healthy for the heart, perpetuated oxalate absorption by further reducing the calcium available to bind oxalate in the gut. All of these factors and possibly the higher concentration of intestinal soluble oxalate11 promoted hyperabsorption of oxalate, which resulted in increased urinary oxalate concentration, with precipitation of calcium oxalate crystals in the renal tubules causing kidney injury.

Introduction and objectives Reactive oxygen species (ROS) are produced during the interaction between oxalate/calcium oxalate monohydrate (COM) crystals and renal epithelial cells and are responsible for the various cellular responses through the activation of NADPH oxidase (Nox). Ox and COM also activate the renin–angiotensin–aldosterone system (RAAS). Aldosterone stimulates ROS production through activation of Nox with the involvement of mineralocorticoid receptor (MR), Rac1 and mitogen-activated protein kinases (MAPK). We investigated RAAS pathways in vivo in an animal model of hyperoxaluria and in vitro by exposing renal epithelial cells to COM crystals. Methods Hyperoxaluria was induced in male SD rats by administering ethylene glycol. One group of rats was additionally given spironolactone. Total RNA was extracted and subjected to genomic microarrays to obtain global transcriptome data. Normal rat kidney cell line (NRK-52E) was incubated with aldosterone(10 −7  M) and COM(67 μg/cm 2 ) with or without spironolactone(10 −5  M), a selective inhibitor of SRC family of kinases; protein phosphatase 2(pp2) (10 −5  M) and Nox inhibitor; diphenylene iodonium (DPI) (10 −5  M). Results Relative expression of genes encoding for AGT, angiotensin receptors 1b and 2, Renin 1, Cyp11b, HSD11B2, Nr3c2, NOx4 and Rac1 was upregulated in the kidneys of rats with hyperoxaluria. Treatment with spironolactone reversed the effect of hyperoxaluria. Both aldosterone and COM crystals activated Nox and Rac1 expression in NRK52E, while spironolactone inhibited Nox and Rac1 expression. Increased Rac1 expression was significantly attenuated by treatment with PP2 and spironolactone. Conclusions Results indicate that hyperoxaluria-induced production of ROS, injury and inflammation are in part associated with the activation of Nox through renin–angiotensin–aldosterone pathway.