Transcriptional adaptation to Clcn5 knockout in proximal tubules of mouse kidney

Wright, Jerry; Morales, Marcelo M.; Sousa-Menzes, Jackson; Ornellas, Débora S.; Sipes, Jennifer; Cui, Yan; Cui, Isabelle; Hulamm, Phuson; Cebotaru, Valeriu; Cebotaru, Liudmila; Guggino, William B.; Guggino, Sandra E.

doi:10.1152/physiolgenomics.00024.2008

Cited by 29 publications

(38 citation statements)

References 50 publications

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“…Then, with the aid of a stereoscopic microscope and fine forceps, the proximal tubules were dissected by hand for posterior RNA extraction (Wright et al., 2008). …”

Section: Methodsmentioning

confidence: 99%

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

et al. 2017

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Diabetic nephropathy (DN) occurs in around 40% of those with diabetes. Proteinuria is the main characteristic of DN and develops as a result of increased permeability of the glomerulus capillary wall and/or decreased proximal tubule endocytosis. The goal of this work was to evaluate renal function and the expression of megalin, cubilin, CFTR (cystic fibrosis transmembrane conductance regulator), and ClC‐5 in the proximal tubule and renal cortex of rats with type 1 diabetes. Male Wistar rats were randomly assigned to control (CTRL) and diabetic (DM) groups for 4 weeks. Renal function was assessed in 24‐h urine sample by calculating clearance and fractional excretion of solutes. The RNA and protein contents of ClC‐5, CFTR, megalin, and cubilin were determined in the renal proximal tubule and cortex using real‐time polymerase chain reaction and western blotting techniques, respectively. The results showed higher creatinine clearance and higher urinary excretion of proteins, albumin, and transferrin in the DM group than in the CTRL group. Furthermore, the renal cortex and proximal tubule of diabetic animals showed downregulation of megalin, cubilin, ClC‐5, and CFTR, critical components of the endocytic apparatus. These data suggest dysfunction in proximal tubule low‐molecular‐weight endocytosis and protein glomerulus filtration in the kidney of diabetic rats.

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“…Then, with the aid of a stereoscopic microscope and fine forceps, the proximal tubules were dissected by hand for posterior RNA extraction (Wright et al., 2008). …”

Section: Methodsmentioning

confidence: 99%

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

et al. 2017

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“…Midkine, which is highly expressed in proximal tubule cells, was downregulated, whereas the mRNA encoding lipocalin 2, which is expressed in the distal nephron, was upregulated [103]. Together with the unchanged serum levels of retinol and the increased amount of retinol binding protein in the urine of KO mice [68], one can suggest a mechanism similar to that described for 1,25(OH) 2 -vitamin D 3 .…”

Section: Hyperphosphaturia Hypercalciuria and Kidney Stones As Indimentioning

confidence: 68%

“…Both enzymes, the vitamin D 3 activating and degrading one, are regulated by PTH, with the transcription of the 25 (OH)-vitamin D 3 -1α-hydroxylase being augmented and the messenger RNA (mRNA) stability of the vitamin D 3 24-hydroxylase being decreased [100][101][102]. Indeed, as predicted by increased urinary PTH concentrations in the ClC-5 KO, 25(OH)-vitamin D 3 -1α-hydroxylase mRNA and protein levels are drastically elevated in KO mice, whereas vitamin D 3 24-hydroxylase mRNA is markedly decreased [18,49,103]. Another, potentially even more important Fig.…”

Section: Hyperphosphaturia Hypercalciuria and Kidney Stones As Indimentioning

confidence: 99%

Physiological roles of CLC Cl−/H+ exchangers in renal proximal tubules

Plans

Rickheit

Jentsch

2008

Pflugers Arch - Eur J Physiol

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The CLC gene family encodes Cl(-) channels or Cl(-)/H(+) exchangers. While our understanding of their structure-function relationship has greatly benefited from the crystal structure of bacterial homologues, human inherited diseases and knock-out mice were crucial in deciphering their physiological roles. Several vesicular CLC Cl(-)/H(+) exchangers are expressed in the proximal tubule (PT). ClC-5 mutations cause Dent's disease which is associated with low molecular weight proteinuria and kidney stones. ClC-5 knock-out mice revealed impaired endocytosis as the primary defect in Dent's disease. It extends to receptor-mediated and fluid-phase endocytosis and entails changes in calciotropic hormones that result in kidney stones. No renal functions could be assigned so far to ClC-3 and ClC-4, which are also expressed in PTs. Loss of ClC-7 or its beta-subunit Ostm1 entails lysosomal storage in the PT, in addition to the neuronal lysosomal storage and osteopetrosis that are the hallmarks of ClC-7/Ostm1 loss in mice and men.

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“…However, the observed discrepancy could be explained by the use of different methodologies of gene ablation, KO versus KD (53). During development, gene ablation can be compensated for by genetic mechanisms that are in many cases poorly understood (21,54,55). Previous studies in mice with Gal3 KO showed involvement of Gal3 in regulating cell differentiation and morphogenesis, which could contribute, among other things, to changes in mast cell physiology (49,56).…”

Section: Discussionmentioning

confidence: 99%

New Regulatory Roles of Galectin-3 in High-Affinity IgE Receptor Signaling

Bambousková

Polakovičová

Hálová

et al. 2016

Molecular and Cellular Biology

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c Aggregation of the high-affinity receptor for IgE (FcRI) in mast cells initiates activation events that lead to degranulation and release of inflammatory mediators. To better understand the signaling pathways and genes involved in mast cell activation, we developed a high-throughput mast cell degranulation assay suitable for RNA interference experiments using lentivirus-based short hairpin RNA (shRNA) delivery. We tested 432 shRNAs specific for 144 selected genes for effects on FcRI-mediated mast cell degranulation and identified 15 potential regulators. In further studies, we focused on galectin-3 (Gal3), identified in this study as a negative regulator of mast cell degranulation. FcRI-activated cells with Gal3 knockdown exhibited upregulated tyrosine phosphorylation of spleen tyrosine kinase and several other signal transduction molecules and enhanced calcium response. We show that Gal3 promotes internalization of IgE-FcRI complexes; this may be related to our finding that Gal3 is a positive regulator of FcRI ubiquitination. Furthermore, we found that Gal3 facilitates mast cell adhesion and motility on fibronectin but negatively regulates antigen-induced chemotaxis. The combined data indicate that Gal3 is involved in both positive and negative regulation of FcRI-mediated signaling events in mast cells. M ast cells are important immune cells involved in multiple biological processes (1, 2). Under pathological conditions, they are responsible for IgE-mediated hyperreactivity and participate in severe diseases, such as allergy and asthma (3). Antigen (Ag)-mediated mast cell activation leads to the release of secretory granules containing a variety of preformed mediators (e.g., histamine and proteases), de novo synthesis of cytokines and chemokines, and enhanced production of arachidonic acid metabolites (4, 5). The principal surface receptor involved in mast cell activation is the high-affinity receptor for IgE (FcεRI), which belongs to the family of multichain immune recognition receptors. FcεRI is a tetrameric complex formed by an IgE-binding ␣ subunit, a signalamplifying ␤ subunit, and a homodimer of disulfide-linked ␥ subunits. Each FcεRI ␤ and ␥ subunit contains one immunoreceptor tyrosine-based activation motif (ITAM), which, after tyrosine phosphorylation, serves as a docking site for other signaling molecules, such as the SRC family kinase LYN or spleen tyrosine kinase (SYK). These two enzymes, together with other kinases, then phosphorylate various adaptor proteins, including linker of activated T cells 1 (LAT1) and LAT2 (also known as non-T cell activation linker [NTAL]). These adaptors are involved in activation of phospholipase C␥ (PLC␥) and subsequent signal transduction events, leading to calcium response and degranulation (6). FcεRI signaling is a complex process that depends on the magnitude of receptor aggregation and a balance between positive and negative signals that determine the extent of the response (7, 8). Although signaling pathways leading to mast cell activation have been extensively...

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Transcriptional adaptation to Clcn5 knockout in proximal tubules of mouse kidney

Cited by 29 publications

References 50 publications

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

Physiological roles of CLC Cl−/H+ exchangers in renal proximal tubules

New Regulatory Roles of Galectin-3 in High-Affinity IgE Receptor Signaling

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