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Qais Al-Awqati

Publications and source records attributed to Qais Al-Awqati.

23 records · Page 2Linked to original sources
PubMed2002

Terminal differentiation of intercalated cells: the role of hensin.

During the response to metabolic acidosis, the intercalated cell of the collecting tubule converts from one that secretes HCO3(-) to one that absorbs HCO3(-) by H(+) secretion. The molecular basis of this complex change in phenotype was studied in an immortalized intercalated cell line. We found that it was induced by secretion, polymerization, and deposition of a protein, which we termed hensin, into the extracellular matrix. Surprisingly, this change in phenotype is identical to terminal differentiation of epithelial cells in that it recapitulated all the characteristics of terminal differentiation, including a change in cell shape, acquisition of specialized apical structures (microvilli and ruffles), and the ability to secrete and endocytose materials in a regulated manner from the apical membrane. Hensin is expressed in most epithelia, and others have discovered that it is deleted in a large number of epithelial tumors. These results suggest that conversion of polarity of the intercalated cells represents a process of terminal differentiation.

Acidosis↗
PubMed2002

Stem cells in the kidney.

The kidney is derived from the ureteric bud and the metanephrogenic mesenchyme, and these two progenitor cells differentiate into more than 26 different cell types in the adult kidney. The ureteric bud contains the precursor of the epithelial cells of the collecting duct and the renal mesenchyme contains precursors of all the epithelia of the rest of the nephron, endothelial cell precursors and stroma cells, but the relatedness among these cells is unclear. A single metanephric mesenchymal cell can generate all the epithelial cells of the nephron (except the collecting duct), indicating that the kidney contains epithelial stem cells. It is currently unknown whether these stem cells also are present in the adult kidney but experience in other organs makes this likely. It also is unclear whether embryonic renal epithelial stem cells can generate other cell types, but preliminary studies in our laboratory suggest that they can differentiate into myofibroblasts, smooth muscle, and perhaps endothelial cells, indicating that they are pluripotent renal stem cells. The important problem to be solved now is the identification and location of adult renal stem cells. This article discusses work done in other organs and in renal development that we believe may be useful for the resolution of this problem.

Animals↗
PubMed2002

Metanephric mesenchyme contains embryonic renal stem cells.

Renal epithelial cells derive from either cells of the metanephric mesenchyme or ureteric bud cells, but the origin of other renal cells is unclear. To test whether metanephric mesenchymal cells generate cells other than epithelial, we examined the developmental potential of a metanephric mesenchymal cell line (7.1.1 cells) and of primary cultures of metanephric mesenchymal cells. 7.1.1 Cells express both mesenchymal and epithelial markers and, on confluence, form well-defined monolayers expressing epithelial junctional proteins. However, 7.1.1 cells as well as primary cultures of metanephric mesenchymal cells also generate spindle-shaped cells that are positive for alpha-smooth muscle actin, indicating that they are myofibroblasts and/or smooth muscle; this differentiation pathway is inhibited by collagen IV and enhanced by fetal calf serum or transforming growth factor-beta(1). Transforming growth factor-beta(1) also induces expression of smooth muscle proteins, indicating that the cells differentiate into smooth muscle. 7.1.1 Cells as well as primary cultures of metanephric mesenchymal cells also express vascular endothelial growth factor receptor 2 and Tie-2, suggesting that the metanephric mesenchymal cells that generate epithelia may also differentiate into endothelial cells. The pluripotency of the 7.1.1 cells is self-renewing. The data suggest that the metanephric mesenchyme contains embryonic renal stem cells.

Animals↗
PubMed2002

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. CCDs maintained 3 h at low pH ex vivo display a reversal of HCO(3)(-) flux that is quantitatively similar to an effect previously observed in acid-treated rabbits in vivo. We followed intracellular pH in the same beta-intercalated cells before and after acid incubation and found that apical Cl/HCO(3) exchange was abolished following acid incubation. Some cells also developed basolateral Cl(-)/HCO(3)(-) exchange, indicating a reversal of intercalated cell polarity. This adaptation required intact microtubules and microfilaments, as well as new protein synthesis, and was associated with decreased size of the apical surface of beta-intercalated cells. Addition of anti-hensin antibodies prevented the acid-induced changes in apical and basolateral Cl(-)/HCO(3)(-) exchange observed in the same cells and the corresponding suppression of HCO(3)(-) secretion. Acid loading also promoted hensin deposition in the ECM underneath adapting beta-intercalated cells. Hence, the adaptive conversion of beta-intercalated cells to alpha-intercalated cells during acid incubation depends upon ECM-associated hensin.

Acid-Base Equilibrium↗