Spns1 is an iron transporter essential for megalin-dependent endocytosis.

Proximal tubule endocytosis is essential to produce protein-free urine as well as to regulate system-wide metabolic pathways, such as the activation of Vitamin D. We have determined that the proximal tubule expresses an endolysosomal membrane protein, protein spinster homolog1 (Spns1), which engenders a novel iron conductance that is indispensable during embryonic development. Conditional knockout of Spns1 with a novel Cre-LoxP construct specific to megalin-expressing cells led to the arrest of megalin receptor-mediated endocytosis as well as dextran pinocytosis in proximal tubules.

Active Tobacco Use in Patients with Claudication Does Not Affect Outcomes after Endovascular Interventions.

Background: With the advent of endovascular procedures, the indications for intervention in claudicants have become less strict. Many interventionalists, however, will not intervene in patients with lifestyle-limiting claudication unless they have discontinued tobacco use. Many patients are unable to comply with this goal, and there is little published evidence to suggest that continued tobacco use results in poorer outcomes.

α-Intercalated cells defend the urinary system from bacterial infection.

α-Intercalated cells (A-ICs) within the collecting duct of the kidney are critical for acid-base homeostasis. Here, we have shown that A-ICs also serve as both sentinels and effectors in the defense against urinary infections. In a murine urinary tract infection model, A-ICs bound uropathogenic E.

Aberrant expression of laminin-332 promotes cell proliferation and cyst growth in ARPKD.

Basement membrane abnormalities have often been observed in kidney cysts of polycystic kidney disease (PKD) patients and animal models. There is an abnormal deposition of extracellular matrix molecules, including laminin-α3,β3,γ2 (laminin-332), in human autosomal dominant PKD (ADPKD). Knockdown of PKD1 paralogs in zebrafish leads to dysregulated synthesis of the extracellular matrix, suggesting that altered basement membrane assembly may be a primary defect in ADPKD.

Galectin-3 mediates oligomerization of secreted hensin using its carbohydrate-recognition domain.

A multidomain, multifunctional 230-kDa extracellular matrix (ECM) protein, hensin, regulates the adaptation of rabbit kidney to metabolic acidosis by remodeling collecting duct intercalated cells. Conditional deletion of hensin in intercalated cells of the mouse kidney leads to distal renal tubular acidosis and to a significant reduction in the number of cells expressing the basolateral chloride-bicarbonate exchanger kAE1, a characteristic marker of α-intercalated cells. Although hensin is secreted as a monomer, its polymerization and ECM assembly are essential for its role in the adaptation of the kidney to metabolic acidosis.

Secreted cyclophilin A, a peptidylprolyl cis-trans isomerase, mediates matrix assembly of hensin, a protein implicated in epithelial differentiation.

Hensin is a rabbit ortholog of DMBT1, a multifunctional, multidomain protein implicated in the regulation of epithelial differentiation, innate immunity, and tumorigenesis. Hensin in the extracellular matrix (ECM) induced morphological changes characteristic of terminal differentiation in a clonal cell line (clone C) of rabbit kidney intercalated cells. Although hensin is secreted in monomeric and various oligomeric forms, only the polymerized ECM form is able to induce these phenotypic changes.

Role of integrins in the assembly and function of hensin in intercalated cells.

Epithelial differentiation proceeds in at least two steps: Conversion of a nonepithelial cell into an epithelial sheet followed by terminal differentiation into the mature epithelial phenotype. It was recently discovered that the extracellular matrix (ECM) protein hensin is able to convert a renal intercalated cell line from a flat, squamous shape into a cuboidal or columnar epithelium. Global knockout of hensin in mice results in embryonic lethality at the time that the first columnar cells appear.

Differentiation of columnar epithelia: the hensin pathway.

Epithelia, the most common variety of cells in complex organisms exist in many shapes. They are sheets of polarized cells that separate two compartments and selectively transport materials from one to the other. After acquiring these general characteristics, they differentiate to become specialized types such as squamous columnar or transitional epithelia.

Galectin-3 expression is induced in renal beta-intercalated cells during metabolic acidosis.

The adaptation of the cortical collecting duct (CCD) to metabolic acidosis requires the polymerization and deposition in the extracellular matrix of the novel protein hensin. HCO3(-)-secreting beta-intercalated cells remove apical Cl-:HCO3(-) exchangers and may reverse functional polarity to secrete protons. Using intercalated cells in culture, we found that galectin-3 facilitated hensin polymerization, thereby causing their differentiation into the H+-secreting cell phenotype.

Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin.

Cyclosporin A (CsA), a widely used immunosuppressant, causes distal renal tubular acidosis (dRTA). It exerts its immunosuppressive effect by a calcineurin-inhibitory complex with its cytosolic receptor, cyclophilin A. However, CsA also inhibits the peptidyl prolyl cis-trans isomerase (PPIase) activity of cyclophilin A.

Terminal differentiation of epithelia from trophectoderm to the intercalated cell: the role of hensin.

The intercalated cells of the collecting tubules of mammalian kidneys were discovered by Haggege and Richet to change their morphology in response to a variety of physiologic stimuli related to changes in acid base status. Recent studies showed that the conversion of beta to alpha intercalated cell under the influence of acidification of the medium is due to the deposition of hensin in the extracellular matrix of these cells and activation of a novel inductive signal transduction pathway. The conversion of beta to alpha cells is shown to be a process of terminal differentiation.

Genomic analysis of alachlor-induced oncogenesis in rat olfactory mucosa.

Alachlor induces olfactory mucosal tumors in rats in a highly ordered temporal process. We used GeneChip analysis to test the hypothesis that histological progression and oncogenic transformation are accompanied by gene expression changes that might yield clues as to the molecular pathogenesis of tumor formation. Acute alachlor exposure caused upregulation of matrix metalloproteinases (MMP)-2 and -9, tissue inhibitor of metalloproteinase-1, carboxypeptidase Z, and other genes related to extracellular matrix homeostasis.

Acid incubation reverses the polarity of intercalated cell transporters, an effect mediated by hensin.

Metabolic acidosis causes a reversal of polarity of HCO(3)(-) flux in the cortical collecting duct (CCD). In CCDs incubated in vitro in acid media, beta-intercalated (HCO(3)(-)-secreting) cells are remodeled to functionally resemble alpha-intercalated (H(+)-secreting) cells. A similar remodeling of beta-intercalated cells, in which the polarity of H(+) pumps and Cl(-)/HCO(3)(-) exchangers is reversed, occurs in cell culture and requires the deposition of polymerized hensin in the ECM.