The Role for HNF-1β-Targeted Collectrin in Maintenance of Primary Cilia and Cell Polarity in Collecting Duct Cells

Abstract

Collectrin, a homologue of angiotensin converting enzyme 2 (ACE2), is a type I transmembrane protein, and we originally reported its localization to the cytoplasm and apical membrane of collecting duct cells. Recently, two independent studies of targeted disruption of collectrin in mice resulted in severe and general defects in renal amino acid uptake. Collectrin has been reported to be under the transcriptional regulation by HNF-1α, which is exclusively expressed in proximal tubules and localized at the luminal side of brush border membranes. The deficiency of collectrin was associated with reduction of multiple amino acid transporters on luminal membranes. In the current study, we describe that collectrin is a target of HNF-1β and heavily expressed in the primary cilium of renal collecting duct cells. Collectrin is also localized in the vesicles near the peri-basal body region and binds to γ-actin-myosin II-A, SNARE, and polycystin-2-polaris complexes, and all of these are involved in intracellular and ciliary movement of vesicles and membrane proteins. Treatment of mIMCD3 cells with collectrin siRNA resulted in defective cilium formation, increased cell proliferation and apoptosis, and disappearance of polycystin-2 in the primary cilium. Suppression of collectrin mRNA in metanephric culture resulted in the formation of multiple longitudinal cysts in ureteric bud branches. Taken together, the cystic change and formation of defective cilium with the interference in the collectrin functions would suggest that it is necessary for recycling of the primary cilia-specific membrane proteins, the maintenance of the primary cilia and cell polarity of collecting duct cells. The transcriptional hierarchy between HNF-1β and PKD (polycystic kidney disease) genes expressed in the primary cilia of collecting duct cells has been suggested, and collectrin is one of such HNF-1β regulated genes.

Collectrin Is Involved in the Development of Salt-Sensitive Hypertension by Facilitating the Membrane Trafficking of Apical Membrane Proteins via Interaction With Soluble N -Ethylmaleiamide-Sensitive Factor Attachment Protein Receptor Complex

“…We also described that collectrin is a target of HNF-1␤ and expressed in apical PMs and primary cilium of renal collecting duct cells. 6 Targeted disruption of HNF-1␣ resulted in diabetes and a renal phenotype with Fanconi syndrome characterized by glucosuria, phosphaturia, calciuria, and aminoaciduria. 7 The renalspecific inactivation of HNF-1␤ causes polycystic kidney disease, and renal cyst formation is accompanied by a drastic defect in the transcriptional activation of HNF-1␤-targeted genes such as collectrin and several polycystic kidney disease-related genes, including Umod, Pkhd1, Pkd2, and Tg737/Polaris.…”

Collectrin and ACE2 in renal and intestinal amino acid transport

“…70 As described more in detail in later paragraphs, Tmem27 has also been shown to be critical for the correct expression of amino acid transporters in kidney. 12,13 Local RAS.…”

The Crumbs complex: from epithelial-cell polarity to retinal degeneration

“…Similarly, both ciliated epithelial cells and PRCs must constantly recycle their apical membrane. Strikingly, apical-membrane specialisations, such as cilia or rhabdomeres, are associated with transport vesicles (Satoh et al, 2005;Zhang et al, 2007). Future work will help to unravel the cellbiological basis that underlies the role of the evolutionarily conserved Crumbs protein complex in a variety of processes, such as epithelial integrity, ciliogenesis and the prevention of retinal degeneration.…”