Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Congenital murine polycystic kidney disease

II. Pathogenesis of tubular cyst formation

Abstract

In the current study, the pathogenesis of proximal tubular cyst formation was studied in an animal model of polycystic kidney disease, the CPK mouse. The specific roles of (a) sodium-potassium adenosine triphosphatase (Na−K ATPase) activity, determined by an enzyme-linked kinetic microassay, (b) proximal tubular epithelial hyperplasia, determined by calculation of mitotic indices, and (c) altered proximal tubular basal lamina formation, determined by immunohistological localization of basal lamina glycoproteins, were investigated at progressive developmental stages of CPK proximal tubular cyst formation. Increases in renal Na−K ATPase were present at the earliest fetal stages of proximal tubular cyst formation, and subsequently paralleled the course of proximal tubular cyst progression. Proximal tubular epithelial hyperplasia, although not present at the earliest stages of cyst formation, was a consistent feature of progressive proximal tubular cystic enlargement. Abnormalities in basal lamina glycoprotein expression were not present at any stage of proximal tubular cyst development. We conclude that increased Na−K ATPase and tubular epithelial hyperplasia are significant features of proximal tubular cyst formation in the CPK mouse.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Zerres K, Volpel MC, Weiss H (1984) Cystic kidneys: genetics, pathologic anatomy, clinical picture, and prenatal diagnosis. Hum Genet 68: 104–135

  2. 2.

    Grantham JJ (1983) Polycystic kidney disease: a predominance of giant nephrons. Am J Physiol 244: F3-F10

  3. 3.

    Welling LW, Grantham JJ (1986) Cystic and developmental diseases of the kidney. In: Brenner BM, Rector FC (eds) The kidney, 3rd edn. Saunders, Philadelphia, pp 1341–1376

  4. 4.

    Sedman A, Bell P, Manco-Johnson M, Schrier R, Warady BA, Heard EO, Butler-Simon N, Gabow P (1987) Autosomal dominant polycystic kidney disease in childhood: a longitudinal study. Kidney Int 31: 1000–10005

  5. 5.

    Grantham JJ, Geiser JL, Evan AP (1987) Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int 31: 1145–1152

  6. 6.

    Avner ED (1987) Polycystic kidney disease: insights from recent experimental investigations. Nephron (in press)

  7. 7.

    Evan AP, Gardner KD Jr (1985) Morphology of polycystic disease in man and experimental models. In: Cummings NB, Klahr S (eds) Chronic renal disease. Plenum Press, New York, pp 55–68

  8. 8.

    Evan AP, Gardner KD Jr, Bernstein J (1979) Polypoid and papillary epithelial hyperplasia: a potential cause of ductal obstruction in adult polycystic disease. Kidney Int 16: 743–750

  9. 9.

    Welling LW, Welling DJ (1985) Kinetics of cyst development in cystic renal disease. In: Cummings NB, Klahr S (eds) Chronic renal disease. Plenum, New York, pp 95–104

  10. 10.

    Carone FA, Rowland RG, Perlman SG, Ganote CE (1974) The pathogenesis of drug induced renal cystic disease. Kidney Int 5: 411–421

  11. 11.

    Kanwar YS, Carone FA (1984) Reversible changes of tubular cell basement membrane in drug-induced renal cystic disease. Kidney Int 26: 35–43

  12. 12.

    Butkowski RJ, Carone FA, Grantham JJ, Hudson BG (1985) Tubular basement membrane changes in 2-amino-4,5-diphenylthiazole induced polycystic disease. Kidney Int 28: 744–751

  13. 13.

    Avner ED, Sweeney WE, Finegold DN, Piesco NP, Ellis D (1985) Sodium-potassium ATPase activity mediates cyst formation in metanephric organ culture. Kidney Int 28: 447–455

  14. 14.

    Avner ED, Sweeney WE, Piesco NP, Ellis D (1987) Triiodothyronine-induced cyst formation in metanephric organ culture: the role of increased Na−K-adenosine triphosphatase activity. J Lab Clin Med 109: 441–454

  15. 15.

    Bennett WM, Wickre CG, Muther RS (1985) Movement of organic molecules into cysts. In: Cummings NB Klahr S (eds) Chronic renal disease. Plenum Press, New York, pp 89–94

  16. 16.

    Preminger GM, Koch WE, Eried FA, McFarland E, Murphy ED, Mandell J (1982) Murine congenital polycystic kidney disease. A model for studying development of cystic disease. J Urol 127: 556–560

  17. 17.

    Nidess R, Koch WE, Fried FA, McFarland E, Mandell J (1984) Development of the embryonic murine kidney in normal and congenital polycystic kidney disease: characterization of a proximal tubular degenerative process as the first observable light microscopic defect. J Urol 131: 156–162

  18. 18.

    Avner ED, Studnicki FC, Young Mc, Sweeney WE, Piesco NP, Ellis D, Fetterman GH (1987) congenital murine polycystic kidney disease. I. The ontogeny of tubular cyst formation. Pediatr Nephrol 1: 587–596

  19. 19.

    Yoda A, Yoda S (1981) A new simple preparation method for Na−K-ATPase-rich membrane fragments. Anal Biochem 110: 82–88

  20. 20.

    Nordling S, Aho S (1981) Fluorimetric microassay of DNA using a modified thiobarbituric acid assay. Anal Biochem 115: 260–266

  21. 21.

    Tsao B, Curthoys NP (1980) The absolute asymmetry of orientation of γ-glutamyltranspeptidase and aminopeptidase on the external surface of the rat renal brush border membrane. J Biol Chem 225: 7708–7711

  22. 22.

    Albert Z, Orlowski M, Szewezuk S (1964) Histochemical and biochemical investigations of γ-glutamyltranspeptidase in the tissues of man and laboratory rodents. Acta Histochem 18: 78–89

  23. 23.

    Curthoys NP, Lowry OH (1973) The distribution of glutaminase isoenzymes in the various structures of the nephron in normal, acidotic, and alkalotic rat kidney. J Biol Chem 248: 162–168

  24. 24.

    Curto KA, Sweeney WE, Avner ED, Piesco NP, Curthoys NP (1987) Immunocytochemical localization of gammaglutamyl-transpeptidase during fetal development of the mouse kidney. J Histochem Cytochem (in press)

  25. 25.

    Carlin B, Jaffe R, Bender B, Chung AE (1981) Entactin, a novel basal lamina-associated sulfated glycoprotein. J Biol Chem 256: 5209–5214

  26. 26.

    Gardner KD Jr, Evan AP (1983) Renal cystic disease induced by diphenylthiazole. Kidney Int 24: 43–52

  27. 27.

    Sokal RR, Rohlf FJ (1981) Biometry: the principles and practice of statistics in biological research, 2nd edn. Freeman, San Francisco, pp 226–231

  28. 28.

    Avner ED, Jaffe R, Temple T, Ellis D, Chung AE (1983) The development of renal basement glycoproteins in metanephric organ culture. Lab Invest 48: 263–268

  29. 29.

    Beyeth Y, Gutman Y (1969) Ontogenesis of microsomal ATPase in the rabbit kidney. Biochim Biophys Acta 191: 193–195

  30. 30.

    Davis PW, Dixon RFL (1971) Selective postnatal development of Na, K, activated adenosine triphosphatase in rabbit kidneys. Proc Soc Exp Biol Med 163: 95–97

  31. 31.

    Dobrovic-Jenik D, Ozegovic B, Milkovic S (1984) Postnatal development of rat kidney plasma membrane Na−K-ATPase. Biol Neonate 46: 115–121

  32. 32.

    Schmidt U, Horster M (1977) Na−K activated ATPase: activity maturation in rabbit nephron segments dissected in vitro. Am J Physiol 233: F55-F60

  33. 33.

    Clark SL (1957) Cellular differentiation in the kidneys of newborn mice studied with the electron microscope. J Biophys Biochem Cytol 3: 349–362

  34. 34.

    Kaji D, Kahn T (1987) Na+−K+ pump in chronic renal failure. Am J Physiol 252: F785-F793

  35. 35.

    Fiehn W (1978) The effect of experimental uremia on potassium activated phosphatase from erythrocyte and cardiac membranes. Clin Chim Acta 84: 149–152

  36. 36.

    Kramer HJ, Backer A, Kruck F (1974) Inhibition of intestinal (Na+−K+)-ATPase in experimental uremia. Clin Chim Acta 50: 13–18

  37. 37.

    Minkoff L, Gaertner G, Darab M, Mercier C, Levin ML (1972) Inhibition of brain sodium-potassium ATPase in uremic rats. J Lab Clin Med 80: 71–78

  38. 38.

    Avner ED, Sweeney WE, Young MC, Ellis D (1987) Na−K ATPase activity modulates congenital murine polycystic kidney disease in vitro. Clin Res 35: 542A

  39. 39.

    Ebihara I, Killen PD, Yamada Y, Martin GR, Brown KS (1987) Sustained expression of basement membrane genes in murine congenital polycystic kidney disease. Kidney Int 31: 165

  40. 40.

    Grantham JJ, Donoso VS, Evan AP, Carone FA, Gardner KD (1987) Viscoelastic properties of tubule basement membranes in experimental renal cystic disease. Kidney Int 32: 187–197

  41. 41.

    Crocker JFS, Blecher SR, Givner ML, McCarthy SC (1987) Polycystic kidney and liver disease and corticosterone changes in the CPK mouse. Kidney Int 31: 1088–1091

  42. 42.

    Avner ED, Piesco NP, Sweeney WE, Studnicki FM, Fetterman GH, Ellis D (1984) Hydrocortisone-induced cystic metanephric maldevelopment in serum-free organ culture. Lab Invest 50: 208–218

  43. 43.

    Freiberg JM, Kinsella J, Sacktor B (1982) Glucocorticoids increase the Na+−H+ exchange and decrease the Na+ gradient-dependent phosphate-uptake systems in renal brush border membrane vesicles. Proc Natl Acad Sci USA 79: 4932–4936

  44. 44.

    Fine LG, Holley RW, Nasri H, Badie-Dezfooly B (1985) BSC-1 growth inhibitor transforms a mitogenic stimulus into a hypertrophic stimulus for renal proximal tubular cells: relationship to Na+/H+ antiport activity. Proc Natl Acad Sci USA 82: 6163–6166

  45. 45.

    Toback FG (1980) Induction of growth in kidney epithelial cells in culture by Na+. Proc Natl Acad Sci USA 77: 6654–6656

  46. 46.

    Ruess L, Cassel D, Rothenberg P, Whiteky B, Mancuso D, Glaser L (1986) Mitogens and ion fluxes. In: Mandel LJ, Benos DJ (eds) The role of membranes in cell growth and differentiation. Academic Press, New York, pp 3–54

  47. 47.

    Igarashi Y, Aperia A, Larsson L, Zetterstrom R (1983) Effect of betamethasone on Na−K-ATPase activity and basal and lateral cell membranes in proximal tubular cells during early development. Am J Physiol 245: F232-F237

  48. 48.

    Kinne R (1985) Transport function of renal cell membranes: sodium cotransport systems. In: Kinne R (ed) Renal biochemistry. Elsevier, Amsterdam, pp 100–143

  49. 49.

    Aronson PS (1981) Identifying secondary active solute transport in epithelia. Am J Physiol 240: F1-F11

  50. 50.

    Grantham JJ, Irish J, Terreros D (1982) Bidirectional fluid transport in proximal tubule. In: Zadunaisky JA (ed) Chloride transport in biological membranes. Academic Press, New York, pp 135–150

Download references

Author information

Correspondence to Ellis D. Avner.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Avner, E.D., Sweeney, W.E., Young, M.C. et al. Congenital murine polycystic kidney disease. Pediatr Nephrol 2, 210–218 (1988). https://doi.org/10.1007/BF00862593

Download citation

Key words

  • Cystic kidney disease
  • Animal models
  • Sodium-potassium ATPase
  • CPK mouse