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TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells.

ABSTRACT: Mutations in the polycystins cause autosomal dominant polycystic kidney disease (ADPKD). Here we show that transmembrane protein 33 (TMEM33) interacts with the ion channel polycystin-2 (PC2) at the endoplasmic reticulum (ER) membrane, enhancing its opening over the whole physiological calcium range in ER liposomes fused to planar bilayers. Consequently, TMEM33 reduces intracellular calcium content in a PC2-dependent manner, impairs lysosomal calcium refilling, causes cathepsins translocation, inhibition of autophagic flux upon ER stress, as well as sensitization to apoptosis. Invalidation of TMEM33 in the mouse exerts a potent protection against renal ER stress. By contrast, TMEM33 does not influence pkd2-dependent renal cystogenesis in the zebrafish. Together, our results identify a key role for TMEM33 in the regulation of intracellular calcium homeostasis of renal proximal convoluted tubule cells and establish a causal link between TMEM33 and acute kidney injury.

SUBMITTER: Arhatte M

PROVIDER: S-EPMC6497644 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells.

Arhatte Malika M Gunaratne Gihan S GS El Boustany Charbel C Kuo Ivana Y IY Moro Céline C Duprat Fabrice F Plaisant Magali M Duval Hélène H Li Dahui D Picard Nicolas N Couvreux Anais A Duranton Christophe C Rubera Isabelle I Pagnotta Sophie S Lacas-Gervais Sandra S Ehrlich Barbara E BE Marchant Jonathan S JS Savage Aaron M AM van Eeden Fredericus J M FJM Wilkinson Robert N RN Demolombe Sophie S Honoré Eric E Patel Amanda A

Nature communications 20190502 1

Mutations in the polycystins cause autosomal dominant polycystic kidney disease (ADPKD). Here we show that transmembrane protein 33 (TMEM33) interacts with the ion channel polycystin-2 (PC2) at the endoplasmic reticulum (ER) membrane, enhancing its opening over the whole physiological calcium range in ER liposomes fused to planar bilayers. Consequently, TMEM33 reduces intracellular calcium content in a PC2-dependent manner, impairs lysosomal calcium refilling, causes cathepsins translocation, in ...[more]

PMID: 31048699

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Project description:BACKGROUND:Intrarenal calcium oxalate (CaOx) crystals induce inflammation and kidney tubular cell injury, which are processes that involve TLR4/NF-?B signalling. A recent genome-wide gene expression profile analysis of Randall's plaques in CaOx stone patients revealed that the expression of the long noncoding RNA H19 was significantly upregulated. However, to date, its role in kidney CaOx stones has not been reported. METHOD:A Gene Expression Omnibus (GEO) dataset was utilized to analyse gene expression profiles. Luciferase reporter, Western blotting, qRT-PCR, immunofluorescence staining and reactive oxygen species (ROS) assays were employed to study the molecular mechanism of HMGB1/TLR4/NF-?B regulation by H19 and miR-216b. In vitro and in vivo assays were performed to further confirm the proinflammatory and prooxidative stress effects. FINDING:H19 expression was significantly increased and positively correlated with the expression levels of HMGB1, TLR4 and NF-?B in Randall's plaques and glyoxylate-induced CaOx nephrocalcinosis mouse models. H19 interacted with miR-216b and suppressed its expression. Additionally, miR-216b inhibited HMGB1 expression by directly binding its 3'-untranslated region. Moreover, H19 downregulation inhibited HMGB1, TLR4 and NF-?B expression and suppressed CaOx nephrocalcinosis-induced renal tubular epithelial cell injury, NADPH oxidase, and oxidative stress in vivo and in vitro. Interestingly, miR-216b inhibition partially reversed the inhibitory effect of H19 knockdown on HMGB1 expression. INTERPRETATION:We determined that H19 might serve as a facilitator in the process of CaOx nephrocalcinosis-induced oxidative stress and renal tubular epithelial cell injury, and we revealed that the interaction between H19 and miR-216b could exert its effect via the HMGB1/TLR4/NF-?B pathway. FUNDING:This work was supported by the National Nature Science Foundation of China (Nos. 8196030190, 8190033175, 81370805, 81470935, 81900645, 81500534, and 81602236).

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TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells.

Publications

TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells.

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