Kidney Development, Regeneration, and Polycystic Kidney Disease in Medaka
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.
KeywordsPolycystic Kidney Disease Congenital Hypothyroidism Mammalian Kidney Neonatal Diabetes Mellitus Mesenchymal Condensate
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