Sequential analysis of kidney stone formation in the Aprt knockout mouse

Andrew Evan, Sharon B. Bledsoe, Bret A. Connors, Li Deng, Li Liang, Changshun Shao, Naomi S. Fineberg, Marc D. Grynpas, Peter J. Stambrook, Shao Youzhi, Amrik Sahota, Jay A. Tischfield

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background. We have previously shown that, as in human adenine phosphoribosyltransferase (APRT) deficiency, Aprt knockout mice form 2,8-dihydroxyadenine (DHA) renal stones. The disease develops earlier and is more severe in male than in female mice. To examine the biological bases for these differences, the area occupied by DHA crystals was quantified in kidney sections from male and female mice (strain 129) aged one day to eight months and this parameter was correlated with changes in renal histopathology. Aprt heterozygous and wild-type mice were used as controls. Methods. Following anesthesia, the left kidney was removed and immediately frozen in dry ice. Unstained cryosections were examined by polarized light to determine total area of birefringent particles. The right kidney was perfused and embedded in plastic, and stained sections were viewed by light microscopy to examine the histopathology and to determine the location of the birefringent particles. A pathological score was assigned to the histological findings. The scores from the right kidney were compared with crystal/particle area in the left kidney, and the data were analyzed using two-way analysis of variance. The chemical composition of the particles was determined by x-ray diffraction analysis. Several stone fragments from the bladder were also examined by scanning electron microscopy (SEM). Results. Crystals were detected in kidney sections from one-to two-day-old Aprt knockout mice. The crystal burden remained low in both sexes throughout the study except in males at the 120- to 240-day period. Furthermore, there was a substantial degree of renal pathology, primarily seen as interstitial fibrosis, in those males with a very high level of stone formation. The crystalline material was identified as 6-amino-2,8(3,9)-purine dione, a tautomeric form of DHA. SEM indicated that the crystals were spherical, with a diameter of 10 to 20 μm. Tissue staining and fixation procedures dramatically reduced the amount of birefringent material in kidney sections. Aprt heterozygotes of both sexes had low levels of crystalline material in the kidneys and no pathology. Birefringent material or pathological changes were not seen in kidneys from wild-type mice. Conclusions. Both male and female Aprt knockout mice accumulate DHA. However, the area occupied by DHA crystals was significantly greater in 120- to 240-day-old males compared with the females of similar age. Also, substantial renal pathology was detected in kidneys of male mice that had very high levels of stone material.

Original languageEnglish
Pages (from-to)910-923
Number of pages14
JournalKidney International
Volume60
Issue number3
DOIs
StatePublished - 2001

Fingerprint

Kidney Calculi
Knockout Mice
Kidney
Pathology
Electron Scanning Microscopy
Dry Ice
129 Strain Mouse
Tissue Fixation
Urinary Bladder Calculi
Light
Heterozygote
Plastics
Microscopy

Keywords

  • Adenine phosphoribosyltransferase deficiency
  • Crystals
  • DHA renal stones
  • Kidney stones
  • Renal histopathology
  • Urolithiasis

ASJC Scopus subject areas

  • Nephrology

Cite this

Evan, A., Bledsoe, S. B., Connors, B. A., Deng, L., Liang, L., Shao, C., ... Tischfield, J. A. (2001). Sequential analysis of kidney stone formation in the Aprt knockout mouse. Kidney International, 60(3), 910-923. https://doi.org/10.1046/j.1523-1755.2001.060003910.x

Sequential analysis of kidney stone formation in the Aprt knockout mouse. / Evan, Andrew; Bledsoe, Sharon B.; Connors, Bret A.; Deng, Li; Liang, Li; Shao, Changshun; Fineberg, Naomi S.; Grynpas, Marc D.; Stambrook, Peter J.; Youzhi, Shao; Sahota, Amrik; Tischfield, Jay A.

In: Kidney International, Vol. 60, No. 3, 2001, p. 910-923.

Research output: Contribution to journalArticle

Evan, A, Bledsoe, SB, Connors, BA, Deng, L, Liang, L, Shao, C, Fineberg, NS, Grynpas, MD, Stambrook, PJ, Youzhi, S, Sahota, A & Tischfield, JA 2001, 'Sequential analysis of kidney stone formation in the Aprt knockout mouse', Kidney International, vol. 60, no. 3, pp. 910-923. https://doi.org/10.1046/j.1523-1755.2001.060003910.x
Evan, Andrew ; Bledsoe, Sharon B. ; Connors, Bret A. ; Deng, Li ; Liang, Li ; Shao, Changshun ; Fineberg, Naomi S. ; Grynpas, Marc D. ; Stambrook, Peter J. ; Youzhi, Shao ; Sahota, Amrik ; Tischfield, Jay A. / Sequential analysis of kidney stone formation in the Aprt knockout mouse. In: Kidney International. 2001 ; Vol. 60, No. 3. pp. 910-923.
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T1 - Sequential analysis of kidney stone formation in the Aprt knockout mouse

AU - Evan, Andrew

AU - Bledsoe, Sharon B.

AU - Connors, Bret A.

AU - Deng, Li

AU - Liang, Li

AU - Shao, Changshun

AU - Fineberg, Naomi S.

AU - Grynpas, Marc D.

AU - Stambrook, Peter J.

AU - Youzhi, Shao

AU - Sahota, Amrik

AU - Tischfield, Jay A.

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N2 - Background. We have previously shown that, as in human adenine phosphoribosyltransferase (APRT) deficiency, Aprt knockout mice form 2,8-dihydroxyadenine (DHA) renal stones. The disease develops earlier and is more severe in male than in female mice. To examine the biological bases for these differences, the area occupied by DHA crystals was quantified in kidney sections from male and female mice (strain 129) aged one day to eight months and this parameter was correlated with changes in renal histopathology. Aprt heterozygous and wild-type mice were used as controls. Methods. Following anesthesia, the left kidney was removed and immediately frozen in dry ice. Unstained cryosections were examined by polarized light to determine total area of birefringent particles. The right kidney was perfused and embedded in plastic, and stained sections were viewed by light microscopy to examine the histopathology and to determine the location of the birefringent particles. A pathological score was assigned to the histological findings. The scores from the right kidney were compared with crystal/particle area in the left kidney, and the data were analyzed using two-way analysis of variance. The chemical composition of the particles was determined by x-ray diffraction analysis. Several stone fragments from the bladder were also examined by scanning electron microscopy (SEM). Results. Crystals were detected in kidney sections from one-to two-day-old Aprt knockout mice. The crystal burden remained low in both sexes throughout the study except in males at the 120- to 240-day period. Furthermore, there was a substantial degree of renal pathology, primarily seen as interstitial fibrosis, in those males with a very high level of stone formation. The crystalline material was identified as 6-amino-2,8(3,9)-purine dione, a tautomeric form of DHA. SEM indicated that the crystals were spherical, with a diameter of 10 to 20 μm. Tissue staining and fixation procedures dramatically reduced the amount of birefringent material in kidney sections. Aprt heterozygotes of both sexes had low levels of crystalline material in the kidneys and no pathology. Birefringent material or pathological changes were not seen in kidneys from wild-type mice. Conclusions. Both male and female Aprt knockout mice accumulate DHA. However, the area occupied by DHA crystals was significantly greater in 120- to 240-day-old males compared with the females of similar age. Also, substantial renal pathology was detected in kidneys of male mice that had very high levels of stone material.

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KW - Adenine phosphoribosyltransferase deficiency

KW - Crystals

KW - DHA renal stones

KW - Kidney stones

KW - Renal histopathology

KW - Urolithiasis

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