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. 1996 Mar 1;97(5):1242–1249. doi: 10.1172/JCI118539

Dissociation of glomerular hypertrophy, cell proliferation, and glomerulosclerosis in mouse strains heterozygous for a mutation (Os) which induces a 50% reduction in nephron number.

C He 1, C Esposito 1, C Phillips 1, R K Zalups 1, D A Henderson 1, G E Striker 1, L J Striker 1
PMCID: PMC507177  PMID: 8636436

Abstract

We reported that the Os mutation in ROP mice induced a 50% reduction in nephron number, glomerular hypertrophy, and severe glomerulosclerosis. We examined two mouse strains with the Os mutation, ROP Os/+ and C57 Os/+ mice, to determine whether the genetic background influenced the development of glomerulosclerosis. Nephron number was decreased by 50% in both ROP Os/+ and C57 Os/+ mice, and a glomerular volume and labeling index were two- to threefold increased in both. Whereas glomerulosclerosis was severe in ROP Os/+ mice, it was absent or minimal in C57 Os/+ mice. ROP Os/+ glomeruli had two- to threefold more type IV collagen, laminin, and tenascin than C57 Os/+ by immunofluorescence microscopy. Glomerular alpha 1IV collagen and tenascin mRNA levels were increased (2.8- and 1.7-fold) in ROP Os/+ and in C57 Os/+ (1.7- and 1.4-fold) mice. Both ROP Os/+ and C57 Os/+ mice had a slight increase (1.5- and 1.7-fold) in 72-kD collagenase mRNA levels. Whereas laminin B1 mRNA levels were twofold higher in ROP +/+ than in C57 +/+ mice, there was no further change in the presence of the Os mutation. Thus, the response to the Os mutation depended on the mouse strain, since severe glomerulosclerosis occurred only in ROP Os/+ mice, even though cell proliferation and glomerular hypertrophy also were present in C57 Os/+ mice.

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Selected References

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  1. Alpers C. E., Hudkins K. L., Gown A. M., Johnson R. J. Enhanced expression of "muscle-specific" actin in glomerulonephritis. Kidney Int. 1992 May;41(5):1134–1142. doi: 10.1038/ki.1992.173. [DOI] [PubMed] [Google Scholar]
  2. Aperia A., Broberger O., Wilton P. Renal functional adaptation in the remnant kidney in patients with renal agenesis and in patients nephrectomized in childhood. Acta Paediatr Scand. 1978 Sep;67(5):611–615. doi: 10.1111/j.1651-2227.1978.tb17811.x. [DOI] [PubMed] [Google Scholar]
  3. Argueso L. R., Ritchey M. L., Boyle E. T., Jr, Milliner D. S., Bergstralh E. J., Kramer S. A. Prognosis of patients with unilateral renal agenesis. Pediatr Nephrol. 1992 Sep;6(5):412–416. doi: 10.1007/BF00873996. [DOI] [PubMed] [Google Scholar]
  4. Baudoin P., Provoost A. P. Effects of age at the time of unilateral nephrectomy and dietary protein on long-term renal function in rats. Pediatr Nephrol. 1993 Oct;7(5):536–542. doi: 10.1007/BF00852539. [DOI] [PubMed] [Google Scholar]
  5. Bhathena D. B., Julian B. A., McMorrow R. G., Baehler R. W. Focal sclerosis of hypertrophied glomeruli in solitary functioning kidneys of humans. Am J Kidney Dis. 1985 May;5(5):226–232. doi: 10.1016/s0272-6386(85)80113-x. [DOI] [PubMed] [Google Scholar]
  6. Bolton W. K., Benton F. R., Maclay J. G., Sturgill B. C. Spontaneous glomerular sclerosis in aging Sprague-Dawley rats. I. Lesions associated with mesangial IgM deposits. Am J Pathol. 1976 Nov;85(2):277–302. [PMC free article] [PubMed] [Google Scholar]
  7. Borch-Johnsen K., Nørgaard K., Hommel E., Mathiesen E. R., Jensen J. S., Deckert T., Parving H. H. Is diabetic nephropathy an inherited complication? Kidney Int. 1992 Apr;41(4):719–722. doi: 10.1038/ki.1992.112. [DOI] [PubMed] [Google Scholar]
  8. Brenner B. M., Chertow G. M. Congenital oligonephropathy and the etiology of adult hypertension and progressive renal injury. Am J Kidney Dis. 1994 Feb;23(2):171–175. [PubMed] [Google Scholar]
  9. Brenner B. M. Nephron adaptation to renal injury or ablation. Am J Physiol. 1985 Sep;249(3 Pt 2):F324–F337. doi: 10.1152/ajprenal.1985.249.3.F324. [DOI] [PubMed] [Google Scholar]
  10. Celsi G., Jakobsson B., Aperia A. Influence of age on compensatory renal growth in rats. Pediatr Res. 1986 Apr;20(4):347–350. doi: 10.1203/00006450-198604000-00018. [DOI] [PubMed] [Google Scholar]
  11. Couser W. G., Stilmant M. M. Mesangial lesions and focal glomerular sclerosis in the aging rat. Lab Invest. 1975 Nov;33(5):491–501. [PubMed] [Google Scholar]
  12. Doi T., Hattori M., Agodoa L. Y., Sato T., Yoshida H., Striker L. J., Striker G. E. Glomerular lesions in nonobese diabetic mouse: before and after the onset of hyperglycemia. Lab Invest. 1990 Aug;63(2):204–212. [PubMed] [Google Scholar]
  13. Doi T., Striker L. J., Kimata K., Peten E. P., Yamada Y., Striker G. E. Glomerulosclerosis in mice transgenic for growth hormone. Increased mesangial extracellular matrix is correlated with kidney mRNA levels. J Exp Med. 1991 May 1;173(5):1287–1290. doi: 10.1084/jem.173.5.1287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Elema J. D., Arends A. Focal and segmental glomerular hyalinosis and sclerosis in the rat. Lab Invest. 1975 Nov;33(5):554–561. [PubMed] [Google Scholar]
  15. Fogo A., Hawkins E. P., Berry P. L., Glick A. D., Chiang M. L., MacDonell R. C., Jr, Ichikawa I. Glomerular hypertrophy in minimal change disease predicts subsequent progression to focal glomerular sclerosis. Kidney Int. 1990 Jul;38(1):115–123. doi: 10.1038/ki.1990.175. [DOI] [PubMed] [Google Scholar]
  16. Gilbert R. E., Tsalamandris C., Bach L. A., Panagiotopoulos S., O'Brien R. C., Allen T. J., Goodall I., Young V., Seeman E., Murray R. M. Long-term glycemic control and the rate of progression of early diabetic kidney disease. Kidney Int. 1993 Oct;44(4):855–859. doi: 10.1038/ki.1993.322. [DOI] [PubMed] [Google Scholar]
  17. Gilbert T., Gaonach S., Moreau E., Merlet-Benichou C. Defect of nephrogenesis induced by gentamicin in rat metanephric organ culture. Lab Invest. 1994 May;70(5):656–666. [PubMed] [Google Scholar]
  18. Gilbert T., Lelievre-Pegorier M., Merlet-Benichou C. Long-term effects of mild oligonephronia induced in utero by gentamicin in the rat. Pediatr Res. 1991 Nov;30(5):450–456. doi: 10.1203/00006450-199111000-00011. [DOI] [PubMed] [Google Scholar]
  19. Glicklich D., Haskell L., Senitzer D., Weiss R. A. Possible genetic predisposition to idiopathic focal segmental glomerulosclerosis. Am J Kidney Dis. 1988 Jul;12(1):26–30. doi: 10.1016/s0272-6386(88)80067-2. [DOI] [PubMed] [Google Scholar]
  20. Grond J., Beukers J. Y., Schilthuis M. S., Weening J. J., Elema J. D. Analysis of renal structural and functional features in two rat strains with a different susceptibility to glomerular sclerosis. Lab Invest. 1986 Jan;54(1):77–83. [PubMed] [Google Scholar]
  21. He C. J., Striker L. J., Tsokos M., Yang C. W., Peten E. P., Striker G. E. Relationships between mesangial cell proliferation and types I and IV collagen mRNA levels in vitro. Am J Physiol. 1995 Sep;269(3 Pt 1):C554–C562. doi: 10.1152/ajpcell.1995.269.3.C554. [DOI] [PubMed] [Google Scholar]
  22. He C., Zalups R. K., Henderson D. A., Striker G. E., Striker L. J. Molecular analysis of spontaneous glomerulosclerosis in Os/+ mice, a model with reduced nephron mass. Am J Physiol. 1995 Aug;269(2 Pt 2):F266–F273. doi: 10.1152/ajprenal.1995.269.2.F266. [DOI] [PubMed] [Google Scholar]
  23. Johnson R. J., Lombardi D., Eng E., Gordon K., Alpers C. E., Pritzl P., Floege J., Young B., Pippin J., Couser W. G. Modulation of experimental mesangial proliferative nephritis by interferon-gamma. Kidney Int. 1995 Jan;47(1):62–69. doi: 10.1038/ki.1995.7. [DOI] [PubMed] [Google Scholar]
  24. Johnson R. J., Raines E. W., Floege J., Yoshimura A., Pritzl P., Alpers C., Ross R. Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med. 1992 May 1;175(5):1413–1416. doi: 10.1084/jem.175.5.1413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jones R. H., Hayakawa H., Mackay J. D., Parsons V., Watkins P. J. Progression of diabetic nephropathy. Lancet. 1979 May 26;1(8126):1105–1106. doi: 10.1016/s0140-6736(79)91788-4. [DOI] [PubMed] [Google Scholar]
  26. Julian B. A., Woodford S. Y., Baehler R. W., McMorrow R. G., Wyatt R. J. Familial clustering and immunogenetic aspects of IgA nephropathy. Am J Kidney Dis. 1988 Nov;12(5):366–370. doi: 10.1016/s0272-6386(88)80026-x. [DOI] [PubMed] [Google Scholar]
  27. Kiprov D. D., Colvin R. B., McCluskey R. T. Focal and segmental glomerulosclerosis and porteinuria associated with unilateral renal agenesis. Lab Invest. 1982 Mar;46(3):275–281. [PubMed] [Google Scholar]
  28. Kreisberg J. I., Karnovsky M. J. Focal glomerular sclerosis in the fawn-hooded rat. Am J Pathol. 1978 Sep;92(3):637–652. [PMC free article] [PubMed] [Google Scholar]
  29. Krolewski A. S., Canessa M., Warram J. H., Laffel L. M., Christlieb A. R., Knowler W. C., Rand L. I. Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med. 1988 Jan 21;318(3):140–145. doi: 10.1056/NEJM198801213180303. [DOI] [PubMed] [Google Scholar]
  30. MacKay K., Striker L. J., Pinkert C. A., Brinster R. L., Striker G. E. Glomerulosclerosis and renal cysts in mice transgenic for the early region of SV40. Kidney Int. 1987 Dec;32(6):827–837. doi: 10.1038/ki.1987.283. [DOI] [PubMed] [Google Scholar]
  31. MacKay K., Striker L. J., Stauffer J. W., Agodoa L. Y., Striker G. E. Relationship of glomerular hypertrophy and sclerosis: studies in SV40 transgenic mice. Kidney Int. 1990 Feb;37(2):741–748. doi: 10.1038/ki.1990.41. [DOI] [PubMed] [Google Scholar]
  32. Matsuyama M., Ogiu T., Kontani K., Yamada C., Kawai M., Hiai H., Nakamura T., Shimizu F., Toyokawa T., Kinoshita Y. Genetic regulation of the development of glomerular sclerotic lesions in the BUF/Mna rat. Nephron. 1990;54(4):334–337. doi: 10.1159/000185890. [DOI] [PubMed] [Google Scholar]
  33. McCurdy F. A., Butera P. J., Wilson R. The familial occurrence of focal segmental glomerular sclerosis. Am J Kidney Dis. 1987 Dec;10(6):467–469. doi: 10.1016/s0272-6386(87)80195-6. [DOI] [PubMed] [Google Scholar]
  34. Pesce C. M., Striker L. J., Peten E., Elliot S. J., Striker G. E. Glomerulosclerosis at both early and late stages is associated with increased cell turnover in mice transgenic for growth hormone. Lab Invest. 1991 Nov;65(5):601–605. [PubMed] [Google Scholar]
  35. Peten E. P., Garcia-Perez A., Terada Y., Woodrow D., Martin B. M., Striker G. E., Striker L. J. Age-related changes in alpha 1- and alpha 2-chain type IV collagen mRNAs in adult mouse glomeruli: competitive PCR. Am J Physiol. 1992 Nov;263(5 Pt 2):F951–F957. doi: 10.1152/ajprenal.1992.263.5.F951. [DOI] [PubMed] [Google Scholar]
  36. Provoost A. P., Baudoin P., De Keijzer M. H., Van Aken M., Molenaar J. C. The role of nephron loss in the progression of renal failure: experimental evidence. Am J Kidney Dis. 1991 May;17(5 Suppl 1):27–32. [PubMed] [Google Scholar]
  37. Remuzzi A., Puntorieri S., Battaglia C., Bertani T., Remuzzi G. Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat. J Clin Invest. 1990 Feb;85(2):541–549. doi: 10.1172/JCI114470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schmidt K., Pesce C., Liu Q., Nelson R. G., Bennett P. H., Karnitschnig H., Striker L. J., Striker G. E. Large glomerular size in Pima Indians: lack of change with diabetic nephropathy. J Am Soc Nephrol. 1992 Aug;3(2):229–235. doi: 10.1681/ASN.V32229. [DOI] [PubMed] [Google Scholar]
  39. Simons J. L., Provoost A. P., De Keijzer M. H., Anderson S., Rennke H. G., Brenner B. M. Pathogenesis of glomerular injury in the fawn-hooded rat: effect of unilateral nephrectomy. J Am Soc Nephrol. 1993 Dec;4(6):1362–1370. doi: 10.1681/ASN.V461362. [DOI] [PubMed] [Google Scholar]
  40. Stewart A. D., Stewart J. Studies on syndrome of diabetes insipidus associated with oligosyndactyly in mice. Am J Physiol. 1969 Oct;217(4):1191–1198. doi: 10.1152/ajplegacy.1969.217.4.1191. [DOI] [PubMed] [Google Scholar]
  41. Striker G. E., Nagle R. B., Kohnen P. W., Smuckler E. A. Response to unilateral nephrectomy in old rats. Arch Pathol. 1969 Apr;87(4):439–442. [PubMed] [Google Scholar]
  42. Viberti G. C. Mechanisms of diabetic renal and cardiovascular disease. Acta Diabetol Lat. 1990 Jul-Sep;27(3):267–276. doi: 10.1007/BF02581339. [DOI] [PubMed] [Google Scholar]
  43. Yang C. W., Hattori M., Vlassara H., He C. J., Carome M. A., Yamato E., Elliot S., Striker G. E., Striker L. J. Overexpression of transforming growth factor-beta 1 mRNA is associated with up-regulation of glomerular tenascin and laminin gene expression in nonobese diabetic mice. J Am Soc Nephrol. 1995 Feb;5(8):1610–1617. doi: 10.1681/ASN.V581610. [DOI] [PubMed] [Google Scholar]
  44. Yang C. W., Striker L. J., Pesce C., Chen W. Y., Peten E. P., Elliot S., Doi T., Kopchick J. J., Striker G. E. Glomerulosclerosis and body growth are mediated by different portions of bovine growth hormone. Studies in transgenic mice. Lab Invest. 1993 Jan;68(1):62–70. [PubMed] [Google Scholar]
  45. Zalups R. K. The Os/+ mouse: a genetic animal model of reduced renal mass. Am J Physiol. 1993 Jan;264(1 Pt 2):F53–F60. doi: 10.1152/ajprenal.1993.264.1.F53. [DOI] [PubMed] [Google Scholar]

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