Knockdown of BBS10 in renal cells affects apical targeting of AQP2: a possible explanation for the polyuria associated with Bardet-Biedl Syndrome

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Abstract

Bardet-Biedl syndrome (BBS) is a autosomal-recessive ciliopathy characterized by defects in multiple organ systems. The clinical phenotype consists of major features that are considered the hallmarks of the disorder: retinal degeneration, obesity, hypogonadism, polydactyly, mental retardation, and renal dysfunction. In particular, polyuria and polydipsia, with impairment of renal concentration capacity, are the earliest signs of renal dysfunction. Multiple lines of evidence have indicated that the BBS phenotype is largely a consequence of ciliary dysfunction since most BBS proteins localize to the basal body and the ciliary axoneme. However, recent evidences revealed that BBS proteins might also be involved in non-ciliary-related microtubule-based transport. Among the 14 identified genes (BBS1-14), mutated in BBS patients, BBS10 alone contribute approximately 20% of all known mutations. In order to investigate whether the polyuria associated with BBS might be related to a defect in the shuttling of the water channel AQP2 in the kidney collecting duct, we studied the effect of selective BBS10 knockdown in AQP2-expressing renal cells. Interestingly, apical surface biotinylation indicated that BBS10 siRNA dramatically and specifically prevented the forskolin-induced exocytosis of AQP2 at the apical membrane. In the same experimental condition, immunofluorescence followed by confocal analysis showed that BBS10 silencing strongly affected the organization of the microtubules cytoskeleton within the cell. As a consequence, we observed that, upon FK, treatment AQP2 mostly redistributed to the basolateral membrane with negligible increase at the apical membrane. Taken together, these results suggest that lost of proper microtubule-based polarized transport in the collecting duct cells cause basolateral misrouting of AQP2 and might explain the polyuria associated with mutations of BBS10 causing BBS.

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  • PROCINO G.;SVELTO M.

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2012

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