Medaka pp 111-130 | Cite as

Kidney Development, Regeneration, and Polycystic Kidney Disease in Medaka

  • Hisashi Hashimoto


Medaka has a pronephros at early larval stages, and thereafter the ­mesonephros develops in the tissues around the pronephric tubule and duct. A marked increase in mesonephric nephrons continues until 2 to 3 months after ­hatching, and consequently the mesonephros consists of 200–300 nephrons on each side. The nephrogenic processes can be histologically featured in the ­developing mesonephros as three distinguishable stages: mesenchymal ­condensation, ­formation of a nephrogenic body, and maturation of the nephron. The appearance of mesenchymal condensates and nephrogenic bodies in the ­interstitial tissue indicates that the de novo nephrogenesis takes place actively. As these nephron precursors are positive for wt1 expression, wt1 could be a good marker of de novo nephrogenesis.

The program for nephron development can be reactivated in medaka during adulthood by artificial injury with chemicals. Intraperitoneal administration of gentamicin, damaging tubules, ducts, and the glomeruli, leads to a significant increase of the mesenchymal condensates and nephrogenic bodies in the injured kidney, which can be also recognized as wt1-positive cell masses. Thus, in contrast to mammals, medaka is capable of regenerating the kidney through de novo nephrogenesis, possibly by recruiting stem cells retained in the interstitial tissue of the adult kidney.

The medaka pc mutant shows lesions quite similar to those of the human genetic disease polycystic kidney disease (PKD): it develops numerous fluid-filled renal cysts and suffers from enlargement of the abdomen. Genetic linkage analysis ­identified the causative gene to be the medaka ortholog of glis3. In humans, the mutations in GLIS3 have been reported to be involved in pathogenesis of pleiotropic genetic diseases including PKD and diabetes. Consistent with the medaka mutant phenotype, glis3 mRNA is expressed in the epithelia of the renal tubule and duct. The cilia in the pronephric tubule are significantly shortened in the pc mutant. Glis3 protein is preferentially located in the cilium of renal epithelial cell. Similar to the other PKD genes reported previously, glis3 may also play a crucial role in the ciliary structure or function.

All the findings suggest that medaka serves as a good model for understanding the process of kidney development and regeneration as well as the pathogenesis of human genetic kidney diseases.


Polycystic Kidney Disease Congenital Hypothyroidism Mammalian Kidney Neonatal Diabetes Mellitus Mesenchymal Condensate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Bisgrove BW, Yost HJ (2006) The roles of cilia in developmental disorders and disease. Development (Camb) 133:4131–4143CrossRefGoogle Scholar
  2. Cantley LG (2005) Adult stem cells in the repair of the injured renal tubule. Nat Clin Pract Nephrol 1:22–32PubMedCrossRefGoogle Scholar
  3. Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hiesberger T, Igarashi P, Bennett AM, Ibraghimov-Beskrovnaya O, Somlo S, Caplan MJ (2004) Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. J Clin Invest 114:1433–1443PubMedGoogle Scholar
  4. Cormier SM, Neiheisel TW, Racine RN, Reimschussel R (1995) New nephron development in fish from polluted waters: a possible biomarker. Ecotoxicology 4:157–168CrossRefGoogle Scholar
  5. Drummond I (2003) The skate weighs in on kidney regeneration. J Am Soc Nephrol 14:1704–1705PubMedCrossRefGoogle Scholar
  6. Drummond IA, Majumdar A, Hentschel H, Elger M, Solnica-Krezel L, Schier AF, Neuhauss SC, Stemple DL, Zwartkruis F, Rangini Z, Driever W, Fishman MC (1998) Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function. Development (Camb) 125:4655–4667Google Scholar
  7. Elger M, Hentschel H, Litteral J, Wellner M, Kirsch T, Luft FC, Haller H (2003) Nephrogenesis is induced by partial nephrectomy in the elasmobranch Leucoraja erinacea. J Am Soc Nephrol 14:1506–1518PubMedCrossRefGoogle Scholar
  8. Fedorova S, Miyamoto R, Harada T, Isogai S, Hashimoto H, Ozato K, Wakamatsu Y (2008) Renal glomerulogenesis in medaka fish, Oryzias latipes. Dev Dyn 237:2342–2352PubMedCrossRefGoogle Scholar
  9. Gilbert SF (2003) Developmental biology. Sinauer, SunderlandGoogle Scholar
  10. Harder W (1975) Anatomy of fishes. Schweizerbart, StuttgartGoogle Scholar
  11. Hickman CPJ, Trump BF (1969) The kidney. In: Hoar WS, Randall DJ (eds) Fish physiology. Academic Press, New York, pp 91–239Google Scholar
  12. Igarashi P, Somlo S (2002) Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol 13:2384–2398PubMedCrossRefGoogle Scholar
  13. Igarashi P, Somlo S (2007) Polycystic kidney disease. J Am Soc Nephrol 18:1371–1373PubMedCrossRefGoogle Scholar
  14. Kang HS, Beak JY, Kim YS, Herbert R, Jetten AM (2009) Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease. Mol Cell Biol 29:2556–2569PubMedCrossRefGoogle Scholar
  15. Karp R, Brasel JA, Winick M (1971) Compensatory kidney growth after uninephrectomy in adult and infant rats. Am J Dis Child 121:186–188PubMedGoogle Scholar
  16. Kim YS, Lewandoski M, Perantoni AO, Kurebayashi S, Nakanishi G, Jetten AM (2002) Identification of Glis1, a novel Gli-related, Kruppel-like zinc finger protein containing transactivation and repressor functions. J Biol Chem 277:30901–30913PubMedCrossRefGoogle Scholar
  17. Kim YS, Nakanishi G, Lewandoski M, Jetten AM (2003) GLIS3, a novel member of the GLIS subfamily of Kruppel-like zinc finger proteins with repressor and activation functions. Nucleic Acids Res 31:5513–5525PubMedCrossRefGoogle Scholar
  18. Kim SC, Kim YS, Jetten AM (2005) Kruppel-like zinc finger protein Gli-similar 2 (Glis2) represses transcription through interaction with C-terminal binding protein 1 (CtBP1). Nucleic Acids Res 33:6805–6815PubMedCrossRefGoogle Scholar
  19. Kramer-Zucker AG, Olale F, Haycraft CJ, Yoder BK, Schier AF, Drummond IA (2005) Cilia-driven fluid flow in the zebrafish pronephros, brain and Kupffer’s vesicle is required for normal organogenesis. Development (Camb) 132:1907–1921CrossRefGoogle Scholar
  20. Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993) WT-1 is required for early kidney development. Cell 74:679–691PubMedCrossRefGoogle Scholar
  21. Lagler KF, Bardach JE, Miller RR, May Passino DR (1977) Ichthyology. Wiley, New YorkGoogle Scholar
  22. Lin F, Moran A, Igarashi P (2005) Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney. J Clin Invest 115:1756–1764PubMedCrossRefGoogle Scholar
  23. Mochizuki E, Fukuta K, Tada T, Harada T, Watanabe N, Matsuo S, Hashimoto H, Ozato K, Wakamatsu Y (2005) Fish mesonephric model of polycystic kidney disease in medaka (Oryzias latipes) pc mutant. Kidney Int 68:23–34Google Scholar
  24. Nauli SM, Zhou J (2004) Polycystins and mechanosensation in renal and nodal cilia. BioEssays 26:844–856PubMedCrossRefGoogle Scholar
  25. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137PubMedCrossRefGoogle Scholar
  26. Omran H, Kobayashi D, Olbrich H, Tsukahara T, Loges NT, Hagiwara H, Zhang Q, Leblond G, O’Toole E, Hara C, Mizuno H, Kawano H, Fliegauf M, Yagi T, Koshida S, Miyawaki A, Zentgraf H, Seithe H, Reinhardt R, Watanabe Y, Kamiya R, Mitchell DR, Takeda H (2008) Ktu/PF13 is required for cytoplasmic pre-assembly of axonemal dyneins. Nature (Lond) 456:611–616CrossRefGoogle Scholar
  27. Perner B, Englert C, Bollig F (2007) The Wilms tumor genes wt1a and wt1b control different steps during formation of the zebrafish pronephros. Dev Biol 309:87–96PubMedCrossRefGoogle Scholar
  28. Reimschuessel R (2001) A fish model of renal regeneration and development. ILAR J 42:285–291PubMedCrossRefGoogle Scholar
  29. Reimschuessel R, Biggs K (1996) Zebrafish model for nephron regeneration following injury. Cold Spring Harbor Symposium on Zebrafish Development and Genetics. Cold Spring Harbor, New YorkGoogle Scholar
  30. Reimschuessel R, Bennett RO, May EB, Lipsky MM (1990) Development of newly formed nephrons in the goldfish kidney following hexachlorobutadiene-induced nephrotoxicity. Toxicol Pathol 18:32–38PubMedGoogle Scholar
  31. Reimschuessel R, Bennett RO, May EA, Lipsky MM (1993) Pathological alterations and new nephron development in rainbow trout Oncorhynchus mykiss following tetrachloroethylene contamination. J Zoo Anim Med 24:503–507Google Scholar
  32. Ricardo SD, Deane JA (2005) Adult stem cells in renal injury and repair. Nephrology (Carlton) 10:276–282CrossRefGoogle Scholar
  33. Rookmaaker MB, Smits AM, Tolboom H, Van’t Wout K, Martens AC, Goldschmeding R, Joles JA, Van Zonneveld AJ, Grone HJ, Rabelink TJ, Verhaar MC (2003) Bone-marrow-derived cells contribute to glomerular endothelial repair in experimental glomerulonephritis. Am J Pathol 163:553–562PubMedCrossRefGoogle Scholar
  34. Salice CJ, Rokous JS, Kane AS, Reimschuessel R (2001) New nephron development in goldfish (Carassius auratus) kidneys following repeated gentamicin-induced nephrotoxicosis. Comp Med 51:56–59PubMedGoogle Scholar
  35. Senee V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec JC, Charon C, Nicolino M, Boileau P, Cavener DR, Bougneres P, Taha D, Julier C (2006) Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 38:682–687PubMedCrossRefGoogle Scholar
  36. Serluca FC, Fishman MC (2001) Pre-pattern in the pronephric kidney field of zebrafish. Development (Camb) 128:2233–2241Google Scholar
  37. Taulman PD, Haycraft CJ, Balkovetz DF, Yoder BK (2001) Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. Mol Biol Cell 12:589–599PubMedGoogle Scholar
  38. Tobin JL, Beales PL (2007) Bardet–Biedl syndrome: beyond the cilium. Pediatr Nephrol 22:926–936PubMedCrossRefGoogle Scholar
  39. Vainio S, Lin Y (2002) Coordinating early kidney development: lessons from gene targeting. Nat Rev Genet 3:533–543PubMedCrossRefGoogle Scholar
  40. Verghese E, Weidenfeld R, Bertram JF, Ricardo SD, Deane JA (2008) Renal cilia display length alterations following tubular injury and are present early in epithelial repair. Nephrol Dial Transplant 23:834–841PubMedCrossRefGoogle Scholar
  41. Wang S, Luo Y, Wilson PD, Witman GB, Zhou J (2004) The autosomal recessive polycystic ­kidney disease protein is localized to primary cilia, with concentration in the basal body area. J Am Soc Nephrol 15:592–602PubMedCrossRefGoogle Scholar
  42. Watanabe N, Kato M, Suzuki N, Inoue C, Fedorova S, Hashimoto H, Maruyama S, Matsuo S, Wakamatsu Y (2009) Kidney regeneration through nephron neogenesis in medaka. Dev Growth Differ 51:135–143PubMedCrossRefGoogle Scholar
  43. Watnick T, Germino G (2003) From cilia to cyst. Nat Genet 34:355–356PubMedCrossRefGoogle Scholar
  44. Yoder BK (2007) Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol 18:1381–1388PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  1. 1.Bioscience and Biotechnology Center,Nagoya UniversityNagoyaJapan

Personalised recommendations