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Integrins, Extracellular Matrix, and Terminal Differentiation of Renal Epithelial Cells

Ambra Pozzi and Roy Zent
JASN June 2008, 19 (6) 1043-1044; DOI: https://doi.org/10.1681/ASN.2008040370
Ambra Pozzi
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Roy Zent
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The mechanism whereby epithelial cells terminally differentiate is an active area of investigation. One potential interface is the spatial and temporal expression of the transmembrane receptors known as integrins and the extracellular matrix (ECM) proteins to which they bind. In this issue of JASN, Vijayakumar et al.1 propose that activation of integrin αvβ1 causes synthesis and deposition of hensin, an ECM protein that forms 50- to 100-nm-long fibers composed of several fibrils. Upon polymerization and deposition into the ECM, hensin binds to α6-containing integrins, a key step in mediating the conversion of epithelial cells to a cuboid-like phenotype capable of apical endocytosis. These novel studies suggest that integrin–hensin interactions play an important role in the terminal differentiation of intercalated cells of the collecting duct.

The collecting system of the kidney is derived from the ureteric bud, which undergoes multiple iterations of branching morphogenesis followed by a phase of growth, maturation, and differentiation.2 Many mechanisms regulate this branching and tubular expansion. Multiple transcription factors, growth factors, ECM proteins, and various cognate receptors play a critical role in these processes. Less information is available on the moieties that halt collecting duct growth and induce terminal differentiation. A number of transcription factors modulate the terminal differentiation of epithelial cells in various nephron segments. In this context, the DNA-binding protein/tumor suppressor p53 is one such factor, and its stabilization by phosphorylation and acetylation enhances the transcription of genes associated with terminal differentiation, including aquaporin 2 and the Na+/K+ ATPase.3,4 In addition, p53 cooperates with at least two other transcription factors, cAMP response element-binding protein and Kruppel-like factor 4, to mediate its transcriptional regulation.5 Another example of transcriptional regulation of collecting duct differentiation is the forkhead transcription factor Foxi1, which mediates differentiation of intercalated cells from precursor epithelial cells. When Foxi1 is deleted in mice, they exhibit impaired expression of intercalated cell–specific genes such as Pendrin, H+-ATPase, and AE1, with no altered expression of principal cell markers.6 Thus, transcriptional processes or factors/co-factors that regulate the nuclear chromatin surrounding transcription are critical for modulating the expression of genes responsible for induction and maintenance of a differentiated cell phenotype.

Among ECM proteins, hensin modulates terminal differentiation by favoring the conversion of β to α intercalated cells through a process that requires polymerization of hensin by galectin 3.7,8 A key question is how hensin might regulate this terminal differentiation of intercalated cells. Although the answer is not clear, some clues are provided by Vijayakumar et al.1 In this study, the authors show that polymerized hensin signals intercalated cells in vitro through α6-containing integrins. Although they were unable to delineate clearly which α6-containing integrin (α6β1 and/or α6β4) mediates this signaling, blocking anti-β1 antibody experiments suggest the hensin-mediated signal is integrin α6β1 independent, which leaves integrin α6β4.

Integrin α6β4 is unique among the 24 known mammalian integrins, because the β4 subunit cytoplasmic tail is composed of 1017 amino acids and has distinctive cytoskeletal and signaling functions.9 Furthermore, the β4 subunit is unique because it promotes the assembly of hemidesmosomes, specialized structures present in epithelial cells that create stable adhesion by connecting the intracellular keratin cytoskeleton to basement membrane.10 Thus, α6β4 not only performs a major adhesive function in cells but also promotes polarization, a final event in epithelial cell differentiation. The highly polarized and tight junction epithelial cells found within the medulla of the kidney certainly benefit from such structures. Although the best described ligand for integrin α6β4 is laminin-332 (also known as laminin-5), it is possible that hensin is also a ligand for this receptor. Alternative explanations could be that hensin interacts with laminin-332, thereby enhancing its interaction with integrin α6β4, or it might induce laminin-322 expression directly.

The mechanisms whereby integrin α6β4 regulates the terminal differentiation of intercalated cells are purely speculative at present. Hemidesmosome formation in epithelial cells along the collecting duct might favor not only cell polarization but also resistance to apoptosis. In this context, nonpolarized cells are sensitive to induction of apoptosis, whereas polarized cells are resistant with ligation of the β4 integrin.11 It is also conceivable that ligation of integrin α6β4 by hensin induces the activation of specific integrin α6β4-mediated signaling pathways, or the β4 subunit works as an “adaptor” for growth factor receptor signaling.9 Both of these pathways might alter the transcription of genes required for the terminal differentiation of intercalated cells.

Although hensin is the first ECM protein shown to regulate terminal differentiation of intercalated cells within the collecting duct, it is highly likely that other ECM proteins along with basement membranes also regulate terminal differentiation of epithelial cells in different segments of the nephron and collecting system. Thus, the novel finding of Vijayakumar et al. suggests a critical role for the spatial/temporal expression of ECM proteins and their receptors in segmental renal function.

DISCLOSURES

None.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related article, “Role of Integrins in the Assembly and Function of Hensin in Intercalated Cells,” on pages 1079–1091.

  • © 2008 American Society of Nephrology

REFERENCES

  1. ↵
    Vijayakumar S, Erdjument-Bromage H, Tempst P, Al-Awqati Q: Role of integrins in the assembly and function of hensin in intercalated cells. J Am Soc Nephrol 19 : 1079 –1091, 2008
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Cebrian C, Borodo K, Charles N, Herzlinger DA: Morphometric index of the developing murine kidney. Dev Dyn 231 : 601 –608, 2004
    OpenUrlCrossRefPubMed
  3. ↵
    Saifudeen Z, Dipp S, El-Dahr SS: A role for p53 in terminal epithelial cell differentiation. J Clin Invest 109 : 1021 –1030, 2002
    OpenUrlCrossRefPubMed
  4. ↵
    El-Dahr SS, Aboudehen K, Saifudeen Z: Transcriptional control of terminal nephron differentiation. Am J Physiol Renal Physiol 2008 , in press
  5. ↵
    Saifudeen Z, Dipp S, Fan H, El-Dahr SS: Combinatorial control of the bradykinin B2 receptor promoter by p53, CREB, KLF-4, and CBP: Implications for terminal nephron differentiation. Am J Physiol Renal Physiol 288 : F899 –F909, 2005
    OpenUrlCrossRefPubMed
  6. ↵
    Blomqvist SR, Vidarsson H, Fitzgerald S, Johansson BR, Ollerstam A, Brown R, Persson AE, Bergstrom GG, Enerback S: Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1. J Clin Invest 113 : 1560 –1570, 2004
    OpenUrlCrossRefPubMed
  7. ↵
    Al-Awqati Q, Vijayakumar S, Takito J: Terminal differentiation of epithelia from trophectoderm to the intercalated cell: the role of hensin. J Am Soc Nephrol 14[Suppl 1] : S16 –S21, 2003
    OpenUrl
  8. ↵
    Hikita C, Vijayakumar S, Takito J, Erdjument-Bromage H, Tempst P, Al-Awqati Q: Induction of terminal differentiation in epithelial cells requires polymerization of hensin by galectin 3. J Cell Biol 151 : 1235 –1246, 2000
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Giancotti FG: Targeting integrin beta4 for cancer and anti-angiogenic therapy. Trends Pharmacol Sci 28 : 506 –511, 2007
    OpenUrlCrossRefPubMed
  10. ↵
    Litjens SH, de Pereda JM, Sonnenberg A: Current insights into the formation and breakdown of hemidesmosomes. Trends Cell Biol 16 : 376 –383, 2006
    OpenUrlCrossRefPubMed
  11. ↵
    Weaver VM, Lelievre S, Lakins JN, Chrenek MA, Jones JC, Giancotti F, Werb Z, Bissell MJ: Beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2 : 205 –216, 2002
    OpenUrlCrossRefPubMed
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Journal of the American Society of Nephrology: 19 (6)
Journal of the American Society of Nephrology
Vol. 19, Issue 6
June 2008
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Integrins, Extracellular Matrix, and Terminal Differentiation of Renal Epithelial Cells
Ambra Pozzi, Roy Zent
JASN Jun 2008, 19 (6) 1043-1044; DOI: 10.1681/ASN.2008040370

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Integrins, Extracellular Matrix, and Terminal Differentiation of Renal Epithelial Cells
Ambra Pozzi, Roy Zent
JASN Jun 2008, 19 (6) 1043-1044; DOI: 10.1681/ASN.2008040370
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