Dissecting the genetic basis of kidney tubule response to hyperoxaluria using chromosome substitution strains

Wiessner, John H.; Garrett, Michael R.; Roman, Richard J.; Mandel, Neil S.

doi:10.1152/ajprenal.00009.2009

Cited by 5 publications

(12 citation statements)

References 33 publications

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“…Tubules were evaluated for the presence of necrosis and degree of dilation. Tubular injury and crystal deposition was evaluated quantitatively using computer imaging to provide a measure of injury compared to controls [4]. …”

Section: Methodsmentioning

confidence: 99%

“…We have recently published a study [4] assessing the development of hyperoxaluria, oxalate induced kidney injury, and retention of calcium oxalate crystals in the Dahl salt-sensitive (SS) and Brown Norway (BN) rats as well as a consomic panel of rats in which chromosomes from the BN rat were transferred onto the SS genetic background [5]. The goal of that study was to identify the chromosomes containing genes that play a role in the physiologic response of the kidney to oxalate.…”

Section: Introductionmentioning

confidence: 99%

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Improved methodology to induce hyperoxaluria without treatment using hydroxyproline

et al. 2011

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The use of hydroxyproline (HP) to generate hyperoxaluria in the rat is a problem because it is impossible to separate the effect of oxalate on renal injury from the effects of HP and the large array of metabolic intermediates formed when HP is converted to oxalate. Previously, the Dahl salt-sensitive (SS) and Brown Norway (BN) rat strains were studied to determine genetic control of resistance or susceptibility to HP-induced renal injury and crystal deposition. To develop a better model to induce hyperoxaluria without causing injury from HP metabolites, animals were fed a diet containing various levels of added oxalate (0, 1, 2, 3, or 5%). After 5 weeks rats were killed and the kidneys were removed for microscopic evaluation of tubule changes and crystal deposition. The 3 and 5% oxalate-fed groups had a substantial increase in urine oxalate, about 50 and 140 µmol/g body weight over controls, respectively. Both the SS and BN 3% oxalate-fed animals showed only slightly elevated tubule area and no crystal deposition. However, BN animals fed 5% oxalate had a dramatic increase in their percent tubule areas compared to control BN rats and treated SS rats. Crystal deposition in the kidneys was only observed in the 5% oxalate-fed groups. The BN kidneys demonstrated a threefold higher crystal deposition compared to oxalate-fed SS rats. We conclude that oxalate-supplemented food is a better method of producing hyperoxaluria in the rat than using HP which may introduce metabolic intermediates injurious to the kidney.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Improved methodology to induce hyperoxaluria without treatment using hydroxyproline

et al. 2011

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“…Using rats, a chromosome substitution experiment was carried out between the Brown Norway rat and the Dahl salt-sensitive rat, in which hyperoxaluria was induced by increasing amounts of hydroxyproline in the diet [17]. Rats were evaluated for degrees of hyperoxaluria, renal injury, and crystal deposition.…”

Section: Gwas and Animal Model Approaches In The Study Of Renal Stonementioning

confidence: 99%

“…Chromosome 2 genes are postulated to contain genes which regulate response to tubular injury, whilst chromosome 2 and 18 genes regulated crystal deposition and retention. Further fine mapping and expression studies are required to identify the individual genes responsible for these responses [17]. …”

Section: Gwas and Animal Model Approaches In The Study Of Renal Stonementioning

confidence: 99%

Renal Stone Disease

Sayer¹

2010

Nephron Physiol

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Background/Aims: Renal stone disease may be seen as a clinical symptom of an underlying pathological process predisposing to crystallization within the renal tract. Renal stones may be comprised of calcium salts, uric acid, cystine and various other insoluble complexes. Nephrolithiasis may be the manifestation of rare single gene disorders or part of more common idiopathic renal stone-forming diseases. Methods and Results: Molecular genetics has allowed significant progress to be made in our understanding of certain stone-forming conditions. The molecular defect underlying single gene disorders often contributes to a significant metabolic risk factor for stone formation. In contrast, idiopathic renal stone formation relates to the interplay of environmental, dietary and genetic factors, with hypercalciuria being the most commonly found metabolic risk factor. Candidate genes for idiopathic stone formers have been identified using numerous approaches, some of which are outlined here. Despite this, the genetic basis underlying familial hypercalciuria and calcium stone formation remains elusive. The molecular basis of other metabolic risk factors such as hyperuricosuria, hyperoxaluria and hypocitraturia is being unraveled and is allowing new insights into renal stone pathogenesis. Conclusion: The discovery of both rare and common molecular defects leading to renal stones will hopefully increase our understanding of the disease pathogenesis. Such knowledge will allow screening for genetic defects and the use of specific drug therapies in order to prevent renal stone formation.

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“…A recent dose-response study (50) showed that ingestion of hydroxyproline (HP) at the 2% level in drinking water by Brown Norway rats is sufficient to produce markedly increased urinary oxalate excretion (compared with controls) within 2 wk and COM crystal deposition in the kidney by 5 wk. EG is metabolized to glycolaldehyde, glycolate, and glyoxylate, which acts as the precursor to oxalate.…”

Section: Com Crystal Accumulation In Kidney Tissuementioning

confidence: 99%

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

McLaren

McMartin

2010

American Journal of Physiology-Renal Physiology

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Li Y, McLaren MC, McMartin KE. Involvement of urinary proteins in the rat strain difference in sensitivity to ethylene glycol-induced renal toxicity. Am J Physiol Renal Physiol 299: F605-F615, 2010. First published June 9, 2010 doi:10.1152/ajprenal.00419.2009 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. calcium oxalate crystals; Tamm-Horsfall protein; osteopontin; macrophage infiltration; inflammation CALCIUM OXALATE MONOHYDRATE (COM) is the most prevalent crystalline constituent in kidney stones. Chronic low-dose administration of ethylene glycol (EG) to rats is often used to model stone formation (13,26). Oxalate metabolism in humans and rats is considered to be similar (25). Chronic hyperoxaluria can induce oxalate crystal aggregate formation in both humans and rats (13, 26), although formation of stones per se in rats is rare and usually requires marked hyperoxaluria. The rat is the most commonly used animal among all animal models for the study of kidney stone disease (28). However, the variant sensitivity to COM accumulation among different rat strains is not widely known. Cruzan et al. (5) reported a strain-related differen...

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Dissecting the genetic basis of kidney tubule response to hyperoxaluria using chromosome substitution strains

Cited by 5 publications

References 33 publications

Improved methodology to induce hyperoxaluria without treatment using hydroxyproline

Improved methodology to induce hyperoxaluria without treatment using hydroxyproline

Renal Stone Disease

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

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