Lipid–Protein Interactions along the Slit Diaphragm of Podocytes

Schermer, Bernhard; Benzing, Thomas

doi:10.1681/asn.2008070694

Cited by 57 publications

(48 citation statements)

References 48 publications

(71 reference statements)

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“…Furthermore, podocin is known to bind to cholesterol and to potentiate diacylglycerol induced TRPC6 currents in an ion channel complex. 42 Therefore, we next analyzed the involvement of podocin in mechanical P 2 X 4 activation. To this end, podocin knockdown podocytes isolated from Nphs2 flox/flox , Cre +/+ mice 31,43 were used and tested for successful in vitro podocin downregulation according to Western blot analysis (Supplemental Figure 7).…”

Section: P 2 X 4 Channels In Podocytes Are Activated Upon Mechanicalmentioning

confidence: 99%

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization

Forst¹,

Olteanu²,

Mollet

et al. 2016

Journal of the American Society of Nephrology

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Podocytes are specialized, highly differentiated epithelial cells in the kidney glomerulus that are exposed to glomerular capillary pressure and possible increases in mechanical load. The proteins sensing mechanical forces in podocytes are unconfirmed, but the classic transient receptor potential channel 6 (TRPC6) interacting with the MEC-2 homolog podocin may form a mechanosensitive ion channel complex in podocytes. Here, we observed that podocytes respond to mechanical stimulation with increased intracellular calcium concentrations and increased inward cation currents. However, TRPC6-deficient podocytes responded in a manner similar to that of control podocytes, and mechanically induced currents were unaffected by genetic inactivation of TRPC1/3/6 or administration of the broad-range TRPC blocker SKF-96365. Instead, mechanically induced currents were significantly decreased by the specific P2X purinoceptor 4 (P2X 4 ) blocker 5-BDBD. Moreover, mechanical P2X 4 channel activation depended on cholesterol and podocin and was inhibited by stabilization of the actin cytoskeleton. Because P2X 4 channels are not intrinsically mechanosensitive, we investigated whether podocytes release ATP upon mechanical stimulation using a fluorometric approach. Indeed, mechanically induced ATP release from podocytes was observed. Furthermore, 5-BDBD attenuated mechanically induced reorganization of the actin cytoskeleton. Altogether, our findings reveal a TRPC channel-independent role of P2X 4 channels as mechanotransducers in podocytes.

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Section: P 2 X 4 Channels In Podocytes Are Activated Upon Mechanicalmentioning

confidence: 99%

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization

Forst¹,

Olteanu²,

Mollet

et al. 2016

Journal of the American Society of Nephrology

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“…Through the interaction with podocin, other essential slit diaphragm proteins, such as nephrin, CD2AP, and TRPC6, are targeted to these multiproteinlipid supercomplexes within the plasma membrane. Formation of these supercomplexes is a prerequisite for proper function of the slit diaphragm signaling platform and the channel function of TRPC6 (8,14,(17)(18)(19).…”

Section: Nephrotic Syndrome (Ns)mentioning

confidence: 99%

A Disease-causing Mutation Illuminates the Protein Membrane Topology of the Kidney-expressed Prohibitin Homology (PHB) Domain Protein Podocin

Schurek

Völker

Tax

et al. 2014

Journal of Biological Chemistry

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Background: Mutations in the stomatin family protein podocin are the most common genetic cause of proteinuria. Results: A conserved proline residue of podocin is essential for its membrane topology. Conclusion: This study confirms a hairpin-like structure of the membrane-attached PHB domain protein and its significance for cholesterol recruitment. Significance: Podocin P118L elucidates the pathogenic implication in kidney disease and identifies a novel family of PHB domain proteins.

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“…3 It has been reported that nephrin is a required structural component of the glomerular slit diaphragm; forms a pore structure capable of restricting the passage of albumin-sized molecules; binds numerous other proteins that are both present at the slit diaphragm and required for a proper filtration barrier; and is a lipid raft-associated signaling molecule at the slit diaphragm that undergoes tyrosine phosphorylation and is linked to the actin cytoskeleton within podocyte foot processes. [4][5][6] Although many questions still remain, these results provide important mechanistic insights into the potential roles of nephrin and the slit diaphragm in maintaining podocyte health and in establishing and maintaining a size-selective barrier to albumin.…”

mentioning

confidence: 92%

Life Without Nephrin

Miner

2012

Journal of the American Society of Nephrology

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Lipid–Protein Interactions along the Slit Diaphragm of Podocytes

Cited by 57 publications

References 48 publications

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization

A Disease-causing Mutation Illuminates the Protein Membrane Topology of the Kidney-expressed Prohibitin Homology (PHB) Domain Protein Podocin

Life Without Nephrin

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