2 Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction 35 and vacuolar megalin distribution, together with the resulting decrease in the receptor quantitative brush border expression will lead eventually to abnormal endocytosis and loss of various proteins, polypeptides and other compounds in urine48. In cystinotic mice, localized megalin expression in PTECs was apparently normal at 3 months of age but suffered a gradual and progressive descent over the course of the next 9 months11. Similarly, human PTECs also showed defective expression and function of megalin in manifesting cystinotic patients in both renal biopsies and isolated cells in culture11,37.In our study the corresponding pathological process started at a much earlier phase in the zebrafish pronephros, which may signify the rapid development of the disease in zebrafish. Whether cystinosin dysfunction affects mammalian pronephros remains unknown, as this structure forms very early during embryonic development, and disappears by the 10th gestational day in mice and the25thgestational day in humans49. Although, the appearance of tissue cystine crystals is a hallmark of cystinosis, we couldn’t observe any in the histopathological sections of the zebrafish larval model. It is perceivable that tissue cystine crystallization is a cumulative process and needs time to develop. For example, in human kidney tissues cystine crystals were not reported before six months of life50and in mice were not visualized before three months in the cornea and six months in the kidney proximal tubules44,51. Cysteamine, the only specific treatment for human cystinosis patients, is not the curative therapy as it mainly targets cystine accumulation. It is not effective in preventing the renal Fanconi syndrome or restoring other pathogenic mechanisms seen in cystinotic cells like enhanced autophagy4,52, or altered vesicle trafficking37. Furthermore, it has many disadvantages such as the strict dose regimen, the bad breath and sweating odours53, and the frequently severe gastrointestinal adverse effects54. These disadvantages greatly affect drug compliance especially in adolescents and young adults55. To avoid such adverse effects many drugs are being investigated to find an alternative therapeutic agent, especially among the structurally related cysteamine analogues and prodrugs56,57. On the other hand, substances targeting pathogenic mechanisms not related to cystine accumulation, such as autophagy and impaired endocytosis, are currently considered as an adjuvant therapy to cystine depletion48,52. The zebrafish model presented in our study is an excellent tool for in vivo testing as it presents many key features of the human renal disease and can be used for the high throughput screening or for a more profound functional drug testing. In conclusion, the ctns‒/‒ zebrafish mutant described here shows early phenotypic characteristics of the human disease including cystine accumulation, enhanced apoptosis, delayed development, increased glomerular permeability, decreased GFR and defective
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