RGD Reference Report - Dissecting the genetic basis of kidney tubule response to hyperoxaluria using chromosome substitution strains. - Rat Genome Database

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

Authors: Wiessner, JH  Garrett, MR  Roman, RJ  Mandel, NS 
Citation: Wiessner JH, etal., Am J Physiol Renal Physiol. 2009 Aug;297(2):F301-6. Epub 2009 Jun 3.
RGD ID: 2313354
Pubmed: PMID:19493966   (View Abstract at PubMed)
PMCID: PMC2724241   (View Article at PubMed Central)
DOI: DOI:10.1152/ajprenal.00009.2009   (Journal Full-text)

Whether genetics may play a role in the pathophysiologic response of kidney tubules to oxalate exposure remains unexplored despite that as many as 15% of the U.S. population annually will experience a kidney stone composed of calcium oxalate. To explore this issue, we utilized a panel of chromosome substitution strains in which one chromosome at a time was transferred from the Brown Norway (BN) rat onto the Dahl salt-sensitive (SS) genetic background. Hyperoxaluria was induced by adding hydroxyproline (HP) to the drinking water. A dose-response (0-2% HP) study found that both SS and BN exhibited the same level of oxalate excretion as HP concentration increased, but only the BN exhibited changes in urothelial pathology and demonstrated crystal deposition at sites of urothelial injury as a function of dose (at 1.5-2.0%). The consomic panel was treated with 2.0% HP and evaluated for hyperoxaluria, renal injury, and crystal deposition. Tubular injury (% Area) and crystal deposition (% Area) were similar between the resistant SS and SS-4, -6, -7, -8, -9, -11, -16, and -20(BN) consomic rats. However, tubular injury was significantly increased in SS-2(BN) compared with the SS parental (9.8 +/- 1.56 and 4.2 +/- 1.09%, respectively). Crystal deposition was observed in SS-2(BN) and SS-18(BN) (4.7 +/- 0.70 and 3.5 +/- 1.3%, respectively) to the same extent as seen in the susceptible BN (3.2 +/- 0.44%). The fact that crystal deposition was observed in SS-18(BN) without extensive overall tubule injury, compared with the more severe widespread tubular injury seen in SS-2(BN), suggests that the underlying mechanism of each locus is different. In conclusion, these studies establish that BN rats demonstrate oxalate-associated pathology and they retain calcium oxalate crystals coincident with urothelial injury but SS rats do not. These observations establish that BN rat chromosome 2 and 18 harbor genes that contribute to these processes.



Disease Annotations    

Phenotype Annotations    

Mammalian Phenotype
hyperoxaluria  (IAGP)
Objects Annotated

Objects referenced in this article
Strain SS-Chr 11BN/Mcwi null Rattus norvegicus
Strain SS-Chr 16BN/Mcwi null Rattus norvegicus
Strain SS-Chr 20BN/Mcwi null Rattus norvegicus
Strain SS-Chr 4BN/Mcwi null Rattus norvegicus
Strain SS-Chr 6BN/Mcwi null Rattus norvegicus
Strain SS-Chr 8BN/Mcwi null Rattus norvegicus
Strain SS/JrHsdMcwi null Rattus norvegicus

Additional Information