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Publication : 3D spheroid defects in NPHP knockdown cells are rescued by the somatostatin receptor agonist octreotide.

First Author  Ghosh AK Year  2012
Journal  Am J Physiol Renal Physiol Volume  303
Issue  8 Pages  F1225-9
PubMed ID  22832925 Mgi Jnum  J:188633
Mgi Id  MGI:5441378 Doi  10.1152/ajprenal.00135.2012
Citation  Ghosh AK, et al. (2012) 3D spheroid defects in NPHP knockdown cells are rescued by the somatostatin receptor agonist octreotide. Am J Physiol Renal Physiol 303(8):F1225-9
abstractText  Ciliopathies are a heterogeneous group of diseases that exhibit broad clinical phenotypes, including renal cysts, retinal degeneration, and cerebellar vermis aplasia. Nephronophthisis (NPHP) is a renal ciliopathy that causes chronic kidney disease and is characterized by kidney cysts at the cortico-medullary border. Among the 10 different disease-causing genes (NPHP1-NPHP10), mutations in NPHP3, NPHP6, or NPHP8 cause the most severe ciliopathy variants of NPHP, Joubert syndrome, and Meckel Syndrome. In this study, we tested the hypothesis that loss of function of these three most severe disease-associated genes leads to morphological defects in a three-dimensional (3D) renal cell culture [murine (m) inner medullary collecting duct (IMCD) 3] model by either lack of cilia formation and/or cell polarity defects. Stable knockdown cell lines were examined in 3D spheroid culture followed by rhodamine-phalloidin staining to assess spheroid architecture. We observed significantly higher percentages of abnormal spheroids for all three stable cell lines compared with control short-hairpin RNA cells. In addition, stable knockdown of Nphp3, Nphp6, and Nphp8 results in reduced cilia numbers and elevated cAMP levels in mIMCD3 cells. We demonstrate that, following gene knockdown of Nphp3, Nphp6, or Nphp8, treatment with the somatostatin agonist octreotide (2 muM) reduces the percentage of abnormal spheroids compared with control. This study reveals that the loss of Nphp3, Nphp6, or Nphp8 leads to cilia abnormalities and cell polarity defects, resulting in spheroid abnormalities, which can be rescued by inhibiting cAMP levels with octreotide treatment.
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