Strain differences in urinary factors that promote calcium oxalate crystal formation in the kidneys of ethylene glycol-treated rats

2009 ◽  
Vol 296 (5) ◽  
pp. F1080-F1087 ◽  
Author(s):  
Yan Li ◽  
Kenneth E. McMartin
Keyword(s):  
Ethylene Glycol ◽  
Calcium Oxalate ◽  
Wistar Rats ◽  
Kidney Tissue ◽  
Wistar Rat ◽  
Crystal Formation ◽  
Rat Strains ◽  
Crystal Deposition ◽  
Caox Crystal ◽  
F344 Rats

Ethylene glycol (EG)-induced hyperoxaluria is the most commonly employed experimental regimen as an animal model of calcium oxalate (CaOx) stone formation. The variant sensitivity to CaOx among different rat strains has not been fully explored, although the Wistar rat is known to accumulate more CaOx in kidney tissue after low-dose EG exposure than in the Fischer 344 (F344) rats. Supersaturation of CaOx in tubular fluid contributes to the amount of CaOx crystal formation in the kidney. We hypothesized that the urinary supersaturation of CaOx in Wistar rats is higher than that of F344 rats, thereby allowing for greater CaOx crystal deposition in the Wistar rat. Age-matched male Wistar and F344 rats were treated with 0.75% EG or drinking water for 8 wk. Twenty-four-hour urine was collected at 0, 2, 4, 6, and 8 wk for analysis of key electrolytes to calculate the CaOx supersaturation. Plasma oxalate level was also measured. Our data confirmed the different sensitivity to renal toxicity from EG between the two rat strains (Wistar > F344). After EG treatment, the plasma oxalate level and urine oxalate excretion were markedly greater in the Wistar rats than in the F344 rats, while urine calcium was slightly decreased in Wistars. Thus, the CaOx supersaturation in urine of Wistar rats was higher, which led to a greater crystal deposition in kidney in Wistar rats. These studies suggest that during EG treatment, changes in urine electrolytes and in CaOx supersaturation occur to a greater extent in the Wistar rat, in agreement with its greater sensitivity to EG toxicity.

Involvement of urinary proteins in the rat strain difference in sensitivity to ethylene glycol-induced renal toxicity

2010 ◽  
Vol 299 (3) ◽  
pp. F605-F615 ◽  
Author(s):  
Yan Li ◽  
Marie C. McLaren ◽  
Kenneth E. McMartin
Keyword(s):  
Ethylene Glycol ◽  
Wistar Rats ◽  
Inflammatory Responses ◽  
Strain Difference ◽  
Kidney Tissue ◽  
Wistar Rat ◽  
Calcium Oxalate Monohydrate ◽  
Macrophage Infiltration ◽  
Urinary Proteins ◽  
F344 Rats

Ethylene glycol (EG) exposure is a common model for kidney stones, because animals accumulate calcium oxalate monohydrate (COM) in kidneys. Wistar rats are more sensitive to EG than Fischer 344 (F344) rats, with greater COM deposition in kidneys. The mechanisms by which COM accumulates differently among strains are poorly understood. Urinary proteins inhibit COM adhesion to renal cells, which could alter COM deposition in kidneys. We hypothesize that COM accumulates more in Wistar rat kidneys because of lower levels of inhibitory proteins in urine. Wistar and F344 rats were treated with 0.75% EG in drinking water for 8 wk. Twenty-four-hour urine was collected every 2 wk for analysis of urinary proteins. Similar studies were conducted for 2 wk using 2% hydroxyproline (HP) as an alternative oxalate source. Total urinary protein was higher in F344 than Wistar rats at all times. Tamm-Horsfall protein was not different between strains. Osteopontin (OPN) levels in Wistar urine and kidney tissue were higher and were further increased by EG treatment. This increase in OPN occurred before renal COM accumulation. Untreated F344 rats showed greater CD45 and ED-1 staining in kidneys than untreated Wistars; in contrast, EG treatment increased CD45 and ED-1 staining in Wistars more than in F344 rats, indicating macrophage infiltration. This increase occurred in parallel with the increase in OPN and before COM accumulation. Like EG, HP induced markedly greater oxalate concentrations in the plasma and urine of Wistar rats compared with F344 rats. These results suggest that OPN upregulation and macrophage infiltration do not completely protect against COM accumulation and may be a response to crystal retention. Because the two oxalate precursors, EG and HP, produced similar elevations of oxalate, the strain difference in COM accumulation may result more so from metabolic differences between strains than from differences in urinary proteins or inflammatory responses.

Low-vitamin E diet exacerbates calcium oxalate crystal formation via enhanced oxidative stress in rat hyperoxaluric kidney

2009 ◽  
Vol 296 (1) ◽  
pp. F34-F45 ◽  
Author(s):  
Ho-Shiang Huang ◽  
Ming-Chieh Ma ◽  
Jun Chen
Keyword(s):  
Oxidative Stress ◽  
Drinking Water ◽  
Vitamin E ◽  
Calcium Oxalate ◽  
Oxidative Enzyme ◽  
Separate Experiment ◽  
Crystal Formation ◽  
Standard Diet ◽  
Crystal Deposition ◽  
Caox Crystal

Vitamin E was previously reported to reduce calcium oxalate (CaOx) crystal formation. This study explored whether vitamin E deficiency affects intrarenal oxidative stress and accelerates crystal deposition in hyperoxaluria. The control (C) group of rats received a standard diet and drinking water, while the experimental groups received 0.75% ethylene glycol (EG) in drinking water for 42 days. Of the latter, one group received a standard diet (EG group), one received a low-vitamin E (LE) diet (EG+LE group), and the last received an LE diet with vitamin E supplement (4 mg) (EG+LE+E group). The C+LE and C+LE+E groups were the specific controls for the last two experimental groups, respectively. In a separate experiment, EG and EG+LE rats were studied on days 3–42 to examine the temporal relationship between oxidative change and crystal formation. Urinary biochemistry and activity/levels of antioxidative and oxidative enzymes in glomeruli and tubulointerstitial specimens (TIS) were examined. In EG rats, CaOx crystal accumulation was associated with low antioxidative enzyme activity in TIS and with increased oxidative enzyme expression in glomeruli. In the EG+LE group, marked changes in antioxidative and oxidative enzyme levels were seen and correlated with massive CaOx deposition and tubular damage. The increased oxidative stress seen with EG+LE treatment was largely reversed by vitamin E supplementation. A temporal study showed that decrease in antioxidative defense and increased free radical formation in the EG+LE group occurred before crystal deposition. This study shows that low vitamin E disrupts the redox balance and causes cell death, thereby favoring crystal formation.

scholarly journals Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys

2020 ◽  
Vol 134 (19) ◽  
pp. 2565-2580
Author(s):  
Yi-Shiou Tseng ◽  
Wen-Bin Wu ◽  
Yun Chen ◽  
Feili Lo Yang ◽  
Ming-Chieh Ma
Keyword(s):  
Small Intestine ◽  
Calcium Oxalate ◽  
Cell Injury ◽  
Crystal Formation ◽  
Crystal Deposition ◽  
Tubular Cells ◽  
Citrate Transporter ◽  
Caox Crystal

Abstract Short bowel (SB) increases the risk of kidney stones. However, the underlying mechanism is unclear. Here, we examined how SB affected renal oxalate and citrate handlings for in vivo hyperoxaluric rats and in vitro tubular cells. SB was induced by small intestine resection in male Wistar rats. Sham-operated controls had no resection. After 7 days of recovery, the rats were divided into control, SB (both fed with distilled water), ethylene glycol (EG), and SB+EG (both fed with 0.75% EG for hyperoxaluric induction) groups for 28 days. We collected the plasma, 24 h of urine, kidney, and intestine tissues for analysis. Hypocitraturia was found and persisted up to 28 days for the SB group. Hypocalcemia and high plasma parathyroid hormone (PTH) levels were found in the 28-day SB rats. SB aggravated EG-mediated oxalate nephropathy by fostering hyperoxaluria and hypocitraturia, and increasing the degree of supersaturation and calcium oxalate (CaOx) crystal deposition. These effects were associated with renal up-regulations of the oxalate transporter solute carrier family 26 (Slc26)a6 and citrate transporter sodium-dependent dicarboxylate cotransporter-1 (NaDC-1) but not Slc26a2. The effects of PTH on the SB kidneys were then examined in NRK-52E tubular cells. Recombinant PTH attenuated oxalate-mediated cell injury and up-regulated NaDC-1 via protein kinase A (PKA) activation. PTH, however, showed no additive effects on oxalate-induced Slc26a6 and NaDC-1 up-regulation. Together, these results demonstrated that renal NaDC-1 upregulation-induced hypocitraturia weakened the defense against Slc26a6-mediated hyperoxaluria in SB kidneys for excess CaOx crystal formation. Increased tubular NaDC-1 expression caused by SB relied on PTH.

Antioxidant therapy prevents ethylene glycol-induced renal calcium oxalate crystal deposition in Wistar rats

2014 ◽  
Vol 46 (6) ◽  
pp. 1231-1238 ◽  
Author(s):  
Mohammad Reza Naghii ◽  
Eslam Eskandari ◽  
Mahmood Mofid ◽  
Mehdi Jafari ◽  
Mohammad Hossein Asadi
Keyword(s):  
Ethylene Glycol ◽  
Calcium Oxalate ◽  
Wistar Rats ◽  
Antioxidant Therapy ◽  
Calcium Oxalate Crystal ◽  
Crystal Deposition

scholarly journals Case Report of a Fatal Antifreeze Ingestion with a Record High Level and Impressive Renal Crystal Deposition

2016 ◽  
Vol 2016 ◽  
pp. 1-3 ◽  
Author(s):  
Heidi L. Erickson
Keyword(s):  
Case Report ◽  
Ethylene Glycol ◽  
Calcium Oxalate ◽  
Cerebral Edema ◽  
Diethylene Glycol ◽  
Significant Morbidity ◽  
Calcium Oxalate Crystal ◽  
Crystal Deposition ◽  
Autopsy Findings ◽  
High Level

Ethylene glycol, methanol, and diethylene glycol are readily available in many household and commercially available products. While these alcohols are relatively nontoxic themselves, their acidic metabolites are toxic and can result in significant morbidity and mortality. Herein we report a lethal case of massive ethylene glycol ingestion in a suicide with a record high level (1254 mg/dL) and images of the histologic examination of the kidneys revealing impressive calcium oxalate crystal deposition. Autopsy findings also showed evidence of mild cerebral edema.

scholarly journals The Protective Roles of Estrogen Receptor β in Renal Calcium Oxalate Crystal Formation via Reducing the Liver Oxalate Biosynthesis and Renal Oxidative Stress-Mediated Cell Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Wei Zhu ◽  
Zhijian Zhao ◽  
Fu-Ju Chou ◽  
Li Zuo ◽  
Tongzu Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Estrogen Receptor ◽  
Nadph Oxidase ◽  
Calcium Oxalate ◽  
Cell Lines ◽  
Ros Production ◽  
Crystal Deposition ◽  
Caox Crystal

Females develop kidney stones less frequently than males do. However, it is unclear if this gender difference is related to altered estrogen/estrogen receptor (ER) signaling. Here, we found that ER beta (ERβ) signals could suppress hepatic oxalate biosynthesis via transcriptional upregulation of the glyoxylate aminotransferase (AGT1) expression. Results from multiple in vitro renal cell lines also found that ERβ could function via suppressing the oxalate-induced injury through increasing the reactive oxygen species (ROS) production that led to a decrease of the renal calcium oxalate (CaOx) crystal deposition. Mechanism study results showed that ERβ suppressed oxalate-induced oxidative stress via transcriptional suppression of the NADPH oxidase subunit 2 (NOX2) through direct binding to the estrogen response elements (EREs) on the NOX2 5′ promoter. We further applied two in vivo mouse models with glyoxylate-induced renal CaOx crystal deposition and one rat model with 5% hydroxyl-L-proline-induced renal CaOx crystal deposition. Our data demonstrated that mice lacking ERβ (ERβKO) as well as mice or rats treated with ERβ antagonist PHTPP had increased renal CaOx crystal deposition with increased urinary oxalate excretion and renal ROS production. Importantly, targeting ERβ-regulated NOX2 with the NADPH oxidase inhibitor, apocynin, can suppress the renal CaOx crystal deposition in the in vivo mouse model. Together, results from multiple in vitro cell lines and in vivo mouse/rat models all demonstrate that ERβ may protect against renal CaOx crystal deposition via inhibiting the hepatic oxalate biosynthesis and oxidative stress-induced renal injury.

scholarly journals Effect of Macrotyloma uniflorum seeds in ethylene glycol induced urolithiasis in rats

2019 ◽  
Vol 12 (4) ◽  
pp. 43-53
Author(s):  
Vaibhavkumar B. Patel ◽  
Niyati Acharya
Keyword(s):  
Ethylene Glycol ◽  
Calcium Oxalate ◽  
Urine Volume ◽  
Crystal Formation ◽  
Significant Activity ◽  
Magnesium Citrate ◽  
Inhibitory Effects ◽  
Calcium Oxalate Crystal ◽  
Macrotyloma Uniflorum ◽  
Urine Serum

Macrotyloma uniflorum Linn. (Fabaceae) seeds are widely used for their diuretic and urolithiatic effects in India. The present study investigated the effect of aqueous extract of Macrotyloma uniflorum seeds (AEMU) on ethylene glycol induced urolithiasis in rats. To induce urolithiasis, 0.75% v/v ethylene glycol was administered orally for 14 days. The curative doses of 400 and 800 mg/kg were administered from 15th to 28th day. On 28th day, 24 hr urine, serum was collected and various biochemical parameters were estimated in urine, serum and kidney homogenate along with histology of kidney. Co-administration of AEMU with ethylene glycol has significantly (p<0.001) increased the urine volume and the level of calculus inhibitors like magnesium, citrate and decreased the level of calculus promoters like calcium, oxalate, uric acid and urea also decreased in crystallria in urine. AEMU supplement also prevented the pathological changes in kidney and increased the glomerulus activity of the kidney. These results indicate that AEMU showed significant activity in urolithiasis which might be due to its diuretic, calcium oxalate crystal formation inhibitory effects and its ability to increase the levels of inhibitors and decrease the level of promoters of urolithiasis.

scholarly journals Genetic Background but Not Intestinal Microbiota After Co-Housing Determines Hyperoxaluria-Related Nephrocalcinosis in Common Inbred Mouse Strains

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiuyue Ma ◽  
Melissa Grigorescu ◽  
Adrian Schreiber ◽  
Ralph Kettritz ◽  
Maja Lindenmeyer ◽  
...  
Keyword(s):  
Intestinal Microbiota ◽  
Genetic Background ◽  
Interstitial Fibrosis ◽  
Inbred Mouse ◽  
Intestinal Microbiome ◽  
Mouse Strains ◽  
Crystal Formation ◽  
Mrna Levels ◽  
Crystal Deposition ◽  
Caox Crystal

Calcium oxalate (CaOx) crystal formation, aggregation and growth is a common cause of kidney stone disease and nephrocalcinosis-related chronic kidney disease (CKD). Genetically modified mouse strains are frequently used as an experimental tool in this context but observed phenotypes may also relate to the genetic background or intestinal microbiota. We hypothesized that the genetic background or intestinal microbiota of mice determine CaOx crystal deposition and thus the outcome of nephrocalcinosis. Indeed, Casp1-/-, Cybb-/- or Casp1-/-/Cybb-/- knockout mice on a 129/C57BL/6J (B6J) background that were fed an oxalate-rich diet for 14 days did neither encounter intrarenal CaOx crystal deposits nor nephrocalcinosis-related CKD. To test our assumption, we fed C57BL/6N (B6N), 129, B6J and Balb/c mice an oxalate-rich diet for 14 days. Only B6N mice displayed CaOx crystal deposits and developed CKD associated with tubular injury, inflammation and interstitial fibrosis. Intrarenal mRNA expression profiling of 64 known nephrocalcinosis-related genes revealed that healthy B6N mice had lower mRNA levels of uromodulin (Umod) compared to the other three strains. Feeding an oxalate-rich diet caused an increase in uromodulin protein expression and CaOx crystal deposition in the kidney as well as in urinary uromodulin excretion in B6N mice but not 129, B6J and Balb/c mice. However, backcrossing 129 mice on a B6N background resulted in a gradual increase in CaOx crystal deposits from F2 to F7, of which all B6N/129 mice from the 7th generation developed CaOx-related nephropathy similar to B6N mice. Co-housing experiments tested for a putative role of the intestinal microbiota but B6N co-housed with 129 mice or B6N/129 (3rd and 6th generation) mice did not affect nephrocalcinosis. In summary, genetic background but not the intestinal microbiome account for strain-specific crystal formation and, the levels of uromodulin secretion may contribute to this phenomenon. Our results imply that only littermate controls of the identical genetic background strain are appropriate when performing knockout mouse studies in this context, while co-housing is optional.

High-Throughput in vitro Gel-Based Plate Assay to Screen for Calcium Oxalate Stone Inhibitors

2021 ◽  
pp. 1-7
Author(s):  
John A. Chmiel ◽  
Gerrit A. Stuivenberg ◽  
Abdulaziz Alathel ◽  
Jaswanth Gorla ◽  
Bernd Grohe ◽  
...  
Keyword(s):  
Calcium Oxalate ◽  
High Throughput ◽  
Current Knowledge ◽  
Medical Condition ◽  
Urinary Calculi ◽  
Sodium Oxalate ◽  
Crystal Formation ◽  
Test Substance ◽  
Caox Crystal

<b><i>Objective:</i></b> Kidney stones are a common medical condition that is increasing in prevalence worldwide. Approximately, ∼80% of urinary calculi are composed of calcium oxalate (CaOx). There is a growing interest toward identifying therapeutic compounds that can inhibit the formation of CaOx crystals. However, some chemicals (e.g., antibiotics and bacterial metabolites) may directly promote crystallization. Current knowledge is limited regarding crystal promoters and inhibitors. Thus, we have developed an in vitro gel-based diffusion model to screen for substances that directly influence CaOx crystal formation. <b><i>Materials and Methods:</i></b> We used double diffusion of sodium oxalate and calcium chloride-loaded paper disks along an agar medium to facilitate the controlled formation of monohydrate and dihydrate CaOx crystals. A third disk was used for the perpendicular diffusion of a test substance to assess its influence on CaOx crystal formation. <b><i>Results:</i></b> We confirmed that citrates and magnesium are effective inhibitors of CaOx crystals. We also demonstrated that 2 strains of uropathogenic <i>Escherichia coli</i> are able to promote crystal formation. While the other tested uropathogens and most antibiotics did not change crystal formation, ampicillin was able to reduce crystallization. <b><i>Conclusion:</i></b> We have developed an inexpensive and high-throughput model to evaluate substances that influence CaOx crystallization.

scholarly journals Calcium oxalate crystal deposition in kidneys of hypercalciuric mice with disrupted type IIa sodium-phosphate cotransporter

2008 ◽  
Vol 294 (5) ◽  
pp. F1109-F1115 ◽  
Author(s):  
Saeed R. Khan ◽  
Patricia A. Glenton
Keyword(s):  
Animal Model ◽  
Calcium Oxalate ◽  
Kidney Stones ◽  
Sodium Phosphate ◽  
Renal Tubules ◽  
Male Mice ◽  
Calcium Oxalate Crystal ◽  
Crystal Deposition ◽  
Caox Crystal ◽  
Local Supersaturation

The most common theories about the pathogenesis of idiopathic kidney stones consider precipitation of calcium phosphate (CaP) within the kidneys critical for the development of the disease. We decided to test the hypothesis that a CaP substrate can promote the deposition of calcium oxalate (CaOx) in the kidneys. Experimental hyperoxaluria was induced by feeding glyoxylate to male mice with knockout (KO) of NaPi IIa (Npt2a), a sodium-phosphate cotransporter. Npt2a KO mice are hypercalciuric and produce CaP deposits in their renal tubules. Experimental hyperoxaluria led to CaOx crystalluria in both the hypercalciuric KO mice and the normocalciuric control B6 mice. Only the KO mice produced CaOx crystal deposits in their kidneys, but the CaOx crystals deposited separately from the CaP deposits. Perhaps CaP deposits were not available for a CaOx overgrowth. These results also validate earlier animal model observations that showed that CaP substrate is not required for renal deposition of CaOx and that other factors, such as local supersaturation, may be involved. The absence of CaOx deposition in the B6 mice despite extreme hyperoxaluria also signifies the importance of both calcium and oxalate in the development of CaOx nephrolithiasis.

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