Plasticity of Intercalated Cell Polarity: Effect of Metabolic Acidosis

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Abstract

The cortical collecting duct (CCD) is capable of secreting H+ or HCO–3 depending on the acid-base status in vivo. Transport is a function of two types of intercalated cells in the CCD: A-intercalated cells secrete H+ and B-intercalated cells secrete HCO–3. Metabolic acidosis results in a decrease in HCO–3 secretion and an increase in H+ secretion by the respective cells. Using a model of metabolic acidosis in vitro, we have shown that the down-regulation of HCO–3 secretion occurs by endocytosis of apical anion exchangers in B-intercalated cells. The finding of basolateral anion exchangers in some adapted B-intercalated cells is consistent with a reversal of functional epithelial polarity. Plasticity of polarity is also observed in cultured intercalated cells: high-density plating results in converting B- to A-intercalated cells via the deposition of the novel protein hensin in the extracellular matrix. A key problem in renal physiology is to investigate the role of hensin in mediating the adaptation of the CCD to acidosis in vitro and in vivo.

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Hensin Remodels the Apical Cytoskeleton and Induces Columnarization of Intercalated Epithelial Cells: Processes that Resemble Terminal Differentiation

S. Vijayakumar, Jiro Takito, Chinami Hikita … (1999)

Intercalated epithelial cells exist in a spectrum of phenotypes; at one extreme, β cells secrete HCO3 by an apical Cl/HCO3 exchanger and a basolateral H+ ATPase. When an immortalized β cell line is seeded at high density it deposits in its extracellular matrix (ECM) a new protein, hensin, which can reverse the polarity of several proteins including the Cl/HCO3 exchanger (an alternately spliced form of band 3) and the proton translocating ATPase. When seeded at low density and allowed to form monolayers these polarized epithelial cells maintain the original distribution of these two proteins. Although these cells synthesize and secrete hensin, it is not retained in the ECM, but rather, hensin is present in a large number of intracellular vesicles. The apical cytoplasm of low density cells is devoid of actin, villin, and cytokeratin19. Scanning electron microscopy shows that these cells have sparse microvilli, whereas high density cells have exuberant apical surface infolding and microvilli. The apical cytoplasm of high density cells contains high levels of actin, cytokeratin19, and villin. The cell shape of these two phenotypes is different with high density cells being tall with a small cross-sectional area, whereas low density cells are low and flat. This columnarization and the remodeling of the apical cytoplasm is hensin-dependent; it can be induced by seeding low density cells on filters conditioned by high density cells and prevented by an antibody to hensin. The changes in cell shape and apical cytoskeleton are reminiscent of the processes that occur in terminal differentiation of the intestine and other epithelia. Hensin is highly expressed in the intestine and prostate (two organs where there is a continuous process of differentiation). The expression of hensin in the less differentiated crypt cells of the intestine and the basal cells of the prostate is similar to that of low density cells; i.e., abundant intracellular vesicles but no localization in the ECM. On the other hand, as in high density cells hensin is located exclusively in the ECM of the terminally differentiated absorptive villus cells and the prostatic luminal cell. These studies suggest that hensin is a critical new molecule in the terminal differentiation of intercalated cell and perhaps other epithelial cells.

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Only multimeric hensin located in the extracellular matrix can induce apical endocytosis and reverse the polarity of intercalated cells.

S. Vijayakumar, Laith Al-Mawsawi, C Hikita … (1999)

When an intercalated epithelial cell line was seeded at low density and allowed to reach confluence, it located the anion exchanger band 3 in the apical membrane and an H+-ATPase in the basolateral membrane. The same clonal cells seeded at high density targeted these proteins to the reverse location. Furthermore, high density cells had vigorous apical endocytosis, and low density cells had none. The extracellular matrix of high density cells was capable of inducing apical endocytosis and relocation of band 3 to the basolateral membrane in low density cells. A 230-kDa extracellular matrix (ECM) protein termed hensin, when purified to near-homogeneity, was able to reverse the phenotype of the low density cells. Antibodies to hensin prevented this effect, indicating that hensin is necessary for conversion of polarity. We show here that hensin was synthesized by both low density and high density cells. Whereas both phenotypes secreted soluble hensin into their media, only high density cells localized it in their ECM. Analysis of soluble hensin by sucrose density gradients showed that low density cells secreted monomeric hensin, and high density cells secreted higher order multimers. When 35S-labeled monomeric hensin was added to high density cells, they induced its aggregation suggesting that the multimerization was catalyzed by surface events in the high density cells. Soluble monomeric or multimeric hensin did not induce apical endocytosis in low density cells, whereas the more polymerized hensin isolated from insoluble ECM readily induced it. These multimers could be disaggregated by sulfhydryl reagents and by dimethylmaleic anhydride, and treatment of high density ECM by these reagents prevented the induction of endocytosis. These results demonstrate that hensin, like several ECM proteins, needs to be precipitated in the ECM to be functional.

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Intracellular Acidification Induces Cl/HCO 3 Exchange Activity in the Basolateral Membrane of β-intercalated Cells of the Rabbit Cortical Collecting Duct

J. Mérot, G. GIEBISCH, G. Giebisch (1997)

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Journal

Journal ID (publisher-id): NEF

Journal ID (nlm-ta): Nephron

Journal ID (doi): 10.1159/issn.1660-8151

Title: Nephron

Publisher: S. Karger AG

ISSN (Print): 1660-8151

ISSN (Electronic): 2235-3186

Publication date Subscription-year: 2001

Publication date (Print): 2001

Publication date (Electronic): 21 March 2001

Volume: 87

Issue: 4

Pages: 304-313

Affiliations

Departments of Pediatrics and Medicine, University of Rochester School of Medicine, Rochester, N.Y., USA

Article

Publisher ID: 45935 Other ID: Nephron 2001;87:304–313

DOI: 10.1159/000045935

PubMed ID: 11287773

SO-VID: 5c3164f8-3faa-440a-b821-e8debb2387f1

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Plasticity of Intercalated Cell Polarity: Effect of Metabolic Acidosis

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Karger: Nephrology

Most cited references 4

Hensin Remodels the Apical Cytoskeleton and Induces Columnarization of Intercalated Epithelial Cells: Processes that Resemble Terminal Differentiation

Only multimeric hensin located in the extracellular matrix can induce apical endocytosis and reverse the polarity of intercalated cells.

Intracellular Acidification Induces Cl/HCO 3 Exchange Activity in the Basolateral Membrane of β-intercalated Cells of the Rabbit Cortical Collecting Duct

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