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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/F301    most recent 00009.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wiessner, J. H. Articles by Mandel, N. S. PubMed PubMed Citation Articles by Wiessner, J. H. Articles by Mandel, N. S.

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

¹Kidney Disease Center, Departments of ²Medicine and ³Physiology, Medical College of Wisconsin and the ⁴Department of Veterans Affairs Medical Center, Milwaukee, Wisconsin

Submitted 6 January 2009 ; accepted in final form 2 June 2009

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.

Dahl S; spontaneously hypertensive rat; congenic strains; kidney stones