[Corrigendum] Vorinostat protects against calcium oxalate­induced kidney injury in mice.

Subsequently to the publication of the above paper, an interested reader has drawn to the authors' attention that, in Fig. 4, there appeared to be an overlap between the data shown in the 4B (OPN/saline) and the 4C (OPN/DMSO) panels, such that these data may have been derived from the same original source even though different experimental conditions were described in the Figure; furthermore, the Fig. 4F (saline) and 4G (DMSO) panels appeared to be very similar, as if they were tissue sections from the same specimen. Upon examining the final proofs of this article, the authors have determined that the immunohistochemical images of the saline groups were incorrectly selected. A further examination of the original data files disclosed that an error had been made in the labelling of some of the original images. The corrected version of Fig. 4, including the correct data for Fig. 4B and F (for the immunostaining of OPN and CD44, respectively, under saline conditions), is shown opposite. Note that these errors did not affect either the results or the conclusions reported in this paper, and all the authors agree to this Corrigendum. The authors are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this Corrigendum, and apologize to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 12: 4291-4297, 2015; DOI: 10.3892/mmr.2015.3964].

Metabolomic analysis reveals a protective effect of Fu-Fang-Jin-Qian-Chao herbal granules on oxalate-induced kidney injury.

Nephrolithiasis is one of the world's major public health burdens with a high incidence and a risk of persistent renal dysfunction. Fu-Fang-Jin-Qian-Chao granules (FFJQC), a traditional Chinese herb formula, is commonly used in treatment of nephrolithiasis. However, the therapeutic mechanism of FFJQC on kidney stone has still been a mystery. The objective of the present study is to explore the therapeutic mechanism of FFJQC on kidney injury and identify unique metabolomics patterns using a mouse model of kidney stone induced by a calcium oxalate (CaOx) deposition. Von Kossa staining and immuno-histopathological staining of osteopontin (OPN), cluster of differentiation 44 (CD44) and calbindin-D28k were conducted on renal sections. Biochemical analysis was performed on serum, urine, and kidney tissues. A metabolomics approach based on ultra-HPLC coupled with quadrupole-TOF-MS (UHPLC-Q-TOF/MS) was used for serum metabolic profiling. The immunohistopathological and biochemical analysis showed the therapeutic benefits of FFJQC. The expression levels of OPN and CD44 were decreased while calbindin-D28k increased after the CaOx injured mice were treated with FFJQC. In addition, total of 81 serum metabolites were identified to be associated with protective effects of FFJQC on CaOx crystal injured mice. Most of these metabolites were involved in purine, amino acid, membrane lipid and energy metabolism. Potential metabolite biomarkers were found for CaOx crystal-induced renal damage. Potential metabolite biomarkers of CaOx crystal-induced renal damage were found. FFJQC shows therapeutic benefits on CaOx crystal injured mice via regulation of multiple metabolic pathways including amino acids, purine, pyrimidine, glycerolipid, arachidonic acid (AA), sphingolipid, glycerophospholipid, and fatty acid.

UPLC/MS-Based Metabolomics Investigation of the Protective Effect of Hydrogen Gas Inhalation on Mice with Calcium Oxalate-Induced Renal Injury.

Hydrogen has a significant protective effect on calcium oxalate-induced renal injury, but its effect on metabolic profiles is unknown. This study showed the effects of hydrogen on serum and urine metabolites in a renal injury model. Ultra-HPLC quadrupole time-of-flight-MS-based metabolomics was used to characterise metabolic variations. Twenty-five serum metabolites and 14 urine metabolites showed differences in the the nitrogen and oxygen inhalation (NO), nitrogen and oxygen inhalation combined with calcium oxalate induction (CaOx), and hydrogen inhalation combined with calcium oxalate induction (HO+CaOx) groups. Nineteen serum metabolites and 7 urine metabolites showed significant restoration to normal levels after hydrogen gas (H2) treatment. These metabolites are primarily related to amino acid metabolism, fatty acid metabolism, and phospholipid metabolism. This study showed that a comprehensive metabolomics approach is an effective strategy to elucidate the mechanisms underlying the effects of hydrogen treatment on calcium oxalate-induced renal injury.

Metabolomics analysis for hydroxy-L-proline-induced calcium oxalate nephrolithiasis in rats based on ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry.

About 80% of kidney stones are composed of calcium oxalate (CaOx) with variable amounts of calcium phosphate, and hyperoxaluria is considered as an important factor of CaOx nephrolithiasis. However, the underlying metabolic mechanisms of CaOx nephrolithiasis remain undefined. In this study, we successfully developed a rat model with hydroxy-L-proline (HLP) -induced CaOx nephrolithiasis. Rats were continuously orally administrated with HLP for 28 days. Urine and blood samples were collected from the rats treated with or without HLP at four different time points. UPLC-Q-TOF/MS was applied to profile the abundances of metabolites. To obtain more comprehensive analysis of metabolic profiling spectrum, combination of RP-LC and HILIC were applied. We identify 42 significant differential metabolites in the urine, and 13 significant differential metabolites in the blood. Pathway analysis revealed that the pathways involved in amino acid metabolism, taurine metabolism, bile acid synthesis, energy metabolism, TCA cycle, purine metabolism, vitamin metabolism, nicotinic acid and nicotinamide metabolism have been modulated by HLP treatment. This study suggested that a number of metabolic pathways are dysfunctional in the HLP induced crystal kidney injury, and further studies on those pathways are warranted to better understand the metabolic mechanism of CaOx nephrolithiasis.

Vorinostat protects against calcium oxalate-induced kidney injury in mice.

The present study aimed to examine the effect of the histone deacetylase inhibitor, vorinostat (SAHA), on renal function in a calcium oxalate crystal mouse model, and to investigate the mechanism underlying the renoprotective effect of SAHA. Calcium oxalate crystal formation was induced in 8 week­old male C57BL/6 mice by administering 100 mg/kg glyoxylate for 7 days. A total of 24 male C57BL/6 mice were randomly divided into a control group and the following experimental groups: 50 mg/kg normal saline + 100 mg/kg glyoxylate; 50 mg/kg dimethyl sulfoxide (DMSO) + 100 mg/kg glyoxylate; and 50 mg/kg SAHA + 100 mg/kg glyoxylate. The mice in each of the experimental groups were injected with the saline, DMSO or SAHA into their abdominal cavities 6 h prior to the glyoxylate injection. The mice were sacrificed after 7 days, following which blood and urine samples were collected. The kidneys were harvested to analyze the levels of calcium concentrations and the levels of malondialdehyde (MDA), superoxide dismutase and glutathione reductase. Immunohistochemical staining and semi­quantitative analyses were performed to detect the expression levels of osteopontin (OPN) and CD44. Renal tubular cell apoptosis was detected using a TUNEL assay. The concentrations of calcium and malondialdehyde were significantly decreased in the SAHA group, and calcium oxalate crystals in the kidney tissue and the expression levels of OPN and CD44 in the SAHA group were lower, compared with the other experimental groups. SAHA significantly reduced the urinary excretion of KIM­1 and renal tubular cell apoptosis. In conclusion, SAHA reduced calcium oxalate crystal deposition and protected against kidney injury.

Inhalation of hydrogen gas ameliorates glyoxylate-induced calcium oxalate deposition and renal oxidative stress in mice.

The aim of this study is to evaluate the protective effect and underlying mechanism of hydrogen gas (H2) to glyoxylate induced renal calcium oxalate (CaOx) crystal deposition in mice. In present work, rodent renal CaOx crystal deposition model was introduced by intra-abdominal injection of glyoxylate (100 mg/kg/d) for 5 days. Two days before administration of glyoxylate, inhalation of H2 for 30 min per day was initiated and continued for 7 days. By the end of the study, the samples of 24 hours urine, serum and renal tissue were collected for biochemical and pathological assay. According to levels of urine calcium excretion, renal calcium deposition, a serum excretion of kidney injury molecule-1 (KIM-1) assay and a TUNEL assay, inhalation of H2 could successfully decrease the CaOx crystallizations and protect against renal injury. Crystal deposition in the kidneys is associated with oxidative stress, which was indicated by increased levels of renal malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) and decreased activities of superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT). These effects were reversed by a high-dose H2 pretreatment. The renal expressions of osteopontin (OPN), CD44, monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10) were markedly increased in glyoxylate-treated mice, and H2 significantly attenuated the increase of OPN, CD44 and MCP-1 but upregulated the expression of IL-10. Our findings demonstrate that inhalation of H2 reduces renal crystallization, renal oxidative injury and inflammation and it may be a candidate agent with few adverse effects for prevention of nephrolithiasis.

Urinary metabonomics elucidate the therapeutic mechanism of Orthosiphon stamineus in mouse crystal-induced kidney injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Orthosiphon stamineus (OS), a traditional Chinese herb, is often used for promoting urination and treating nephrolithiasis. AIM OF THE STUDY: Urolithiasis is a major worldwide public health burden due to its high incidence of recurrence and damage to renal function. However, the etiology for urolithiasis is not well understood. Metabonomics, the systematic study of small molecule metabolites present in biological samples, has become a valid and powerful tool for understanding disease phenotypes. In this study, a urinary metabolic profiling analysis was performed in a mouse model of renal calcium oxalate crystal deposition to identify potential biomarkers for crystal-induced renal damage and the anti-crystal mechanism of OS. MATERIALS AND METHODS: Thirty six mice were randomly divided into six groups including Saline, Crystal, Cystone and OS at dosages of 0.5g/kg, 1g/kg, and 2g/kg. A metabonomics approach using ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was developed to perform the urinary metabolic profiling analysis. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were utilized to identify differences between the metabolic profiles of mice in the saline control group and crystal group. RESULTS: Using partial least squares-discriminant analysis, 30 metabolites were identified as potential biomarkers of crystal-induced renal damage. Most of them were primarily involved in amino acid metabolism, taurine and hypotaurine metabolism, purine metabolism, and the citrate cycle (TCA). After the treatment with OS, the levels of 20 biomarkers had returned to the levels of the control samples. CONCLUSIONS: Our results suggest that OS has a protective effect for mice with crystal-induced kidney injury via the regulation of multiple metabolic pathways primarily involving amino acid, energy and choline metabolism.

Therapeutic effect of Xue Niao An on glyoxylate-induced calcium oxalate crystal deposition based on urinary metabonomics approach.

The anti-nephrolithiasis effect of Xue Niao An (XNA) capsules is explored by analyzing urine metabolic profiles in mouse models, with ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). An animal model of calcium oxalate crystal renal deposition was established in mice by intra-abdominal injection of glyoxylate. Then, treatment with XNA by intra-gastric administration was performed. At the end of the study, calcium deposition in kidney was measured by Von Kossa staining under light microscopy, and the Von Kossa staining changes showed that XNA significantly alleviated the calcium oxalate crystal deposition. Meanwhile, urine samples for fifteen metabolites, including amino acids and fatty acids, with significant differences were detected in the calcium oxalate group, while XNA treatment attenuated metabolic imbalances. Our study indicated that the metabonomic strategy provided comprehensive insight on the metabolic response to XNA treatment of rodent renal calcium oxalate deposition.