Acidosis affects sodium and potassium excretion, likely via the pH sensitivity of ion transporter... more Acidosis affects sodium and potassium excretion, likely via the pH sensitivity of ion transporters. A recent paper shows that β-intercalated cells with deleted H(+)-ATPase release ATP into urine, which induces the production of prostaglandin E2 (PGE2). PGE2 then reduces sodium absorption in the principal cells of the cortical collecting tubule and increases potassium secretion.
Proceedings of the National Academy of Sciences, 1982
Urinary acidification by the turtle bladder is due to a H+-ATPase that is located in the luminal ... more Urinary acidification by the turtle bladder is due to a H+-ATPase that is located in the luminal membrane. The rate of H+ transport is stimulated by an increase in the ambient CO2. Using the fluorescent dye acridine orange, we showed that the mitochondria-rich cell of this equilibrium contains vesicles whose internal pH is acidic. We measured the pH of these vesicles by using endocytosed fluorescein isothiocyanate-labeled dextran and found it to be near 5.0. The pH increased after treatment with protonophores or metabolic inhibitors, suggesting that it was due to a H+ pump rather than to a Donnan effect. In bladders preloaded with fluorescent dextran, CO2 stimulated exocytosis and H+ transport measured simultaneously in the same bladder. The increase in the H+ current correlated well with the extent of exocytosis, and both were inhibited by pretreatment with colchicine. We conclude that the turtle bladder contains an intracellular reserve of vesicles containing H+ pumps and CO2 stimulates rapid fusion of these vesicles with the luminal membrane with consequent insertion of H+ pumps, thereby stimulating H+ secretion across the whole epithelium.
Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatr... more Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.
In the kidney, the slit diaphragm joins adjacent podocytes, forming an epithelial barrier that fi... more In the kidney, the slit diaphragm joins adjacent podocytes, forming an epithelial barrier that filters plasma into the urinary space, yet retains blood cells and proteins within the circulation. In this issue of the JCI, Soda et al. have identified clathrin-mediated endocytosis as a central mechanism by which the function and structural integrity of the slit diaphragm are maintained.
Hensin is a rabbit ortholog of DMBT1, a multifunctional, multidomain protein implicated in the re... more 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. Here we report that hensin secretion and matrix assembly were inhibited by the peptidylprolyl cis-trans isomerase (PPIase) inhibitors cyclosporin A (CsA) and a derivative of cyclosporin A with modifications in the d-Ser side chain (Cs9) but not by the calcineurin pathway inhibitor FK506. PPIase inhibition led to failure of hensin polymerization in the medium and ECM, plus the loss of apical cytoskeleton, apical microvilli, and the columnar epithelial shape of clone C cells. Cyclophilin A was produced and secreted into the media to a much greater extent than cyclophilins B and C. Our results also identified the direct CsA-sensitive interaction of cyclophilin A with hensin, suggesting that cyclophilin A is the PPIase that mediates the polymerization and matrix assembly of hensin. These results are significant because this is the first time a direct role of peptidylprolyl cis-trans isomerase activity has been implicated in the process of epithelial differentiation.
Acidosis affects sodium and potassium excretion, likely via the pH sensitivity of ion transporter... more Acidosis affects sodium and potassium excretion, likely via the pH sensitivity of ion transporters. A recent paper shows that β-intercalated cells with deleted H(+)-ATPase release ATP into urine, which induces the production of prostaglandin E2 (PGE2). PGE2 then reduces sodium absorption in the principal cells of the cortical collecting tubule and increases potassium secretion.
Proceedings of the National Academy of Sciences, 1982
Urinary acidification by the turtle bladder is due to a H+-ATPase that is located in the luminal ... more Urinary acidification by the turtle bladder is due to a H+-ATPase that is located in the luminal membrane. The rate of H+ transport is stimulated by an increase in the ambient CO2. Using the fluorescent dye acridine orange, we showed that the mitochondria-rich cell of this equilibrium contains vesicles whose internal pH is acidic. We measured the pH of these vesicles by using endocytosed fluorescein isothiocyanate-labeled dextran and found it to be near 5.0. The pH increased after treatment with protonophores or metabolic inhibitors, suggesting that it was due to a H+ pump rather than to a Donnan effect. In bladders preloaded with fluorescent dextran, CO2 stimulated exocytosis and H+ transport measured simultaneously in the same bladder. The increase in the H+ current correlated well with the extent of exocytosis, and both were inhibited by pretreatment with colchicine. We conclude that the turtle bladder contains an intracellular reserve of vesicles containing H+ pumps and CO2 stimulates rapid fusion of these vesicles with the luminal membrane with consequent insertion of H+ pumps, thereby stimulating H+ secretion across the whole epithelium.
Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatr... more Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.
In the kidney, the slit diaphragm joins adjacent podocytes, forming an epithelial barrier that fi... more In the kidney, the slit diaphragm joins adjacent podocytes, forming an epithelial barrier that filters plasma into the urinary space, yet retains blood cells and proteins within the circulation. In this issue of the JCI, Soda et al. have identified clathrin-mediated endocytosis as a central mechanism by which the function and structural integrity of the slit diaphragm are maintained.
Hensin is a rabbit ortholog of DMBT1, a multifunctional, multidomain protein implicated in the re... more 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. Here we report that hensin secretion and matrix assembly were inhibited by the peptidylprolyl cis-trans isomerase (PPIase) inhibitors cyclosporin A (CsA) and a derivative of cyclosporin A with modifications in the d-Ser side chain (Cs9) but not by the calcineurin pathway inhibitor FK506. PPIase inhibition led to failure of hensin polymerization in the medium and ECM, plus the loss of apical cytoskeleton, apical microvilli, and the columnar epithelial shape of clone C cells. Cyclophilin A was produced and secreted into the media to a much greater extent than cyclophilins B and C. Our results also identified the direct CsA-sensitive interaction of cyclophilin A with hensin, suggesting that cyclophilin A is the PPIase that mediates the polymerization and matrix assembly of hensin. These results are significant because this is the first time a direct role of peptidylprolyl cis-trans isomerase activity has been implicated in the process of epithelial differentiation.
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Papers by Q. Al-awqati