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Insulin increases filtration barrier permeability via TRPC6-dependent activation of PKGIα signaling pathways
- Source :
- Biochimica et biophysica acta. Molecular basis of disease. 1863(6)
- Publication Year :
- 2016
-
Abstract
- Podocytes are dynamic polarized cells on the surface of glomerular capillaries and an essential component of the glomerular filtration barrier. Insulin increases the activation of protein kinase G type Iα (PKGIα) subunits, leading to podocyte dysfunction. In addition, accumulating evidence suggests that TRPC6 channels are crucial mediators of podocyte calcium handling and involved in the regulation of glomerular filtration. Therefore, we investigated whether TRPC6 is involved in the regulation of filtration barrier permeability by insulin via the PKGIα-dependent manner. TRPC channel inhibitor SKF96365 abolished insulin-dependent glomerular albumin permeability and transepithelial albumin flux in cultured rat podocytes. Insulin-evoked albumin permeability across podocyte monolayers was also blocked using TRPC6 siRNA. The effect of insulin on albumin permeability was mimicked by treating podocytes with TRPC channel activator (oleolyl-2-acetyl-sn-glycerol, OAG). Insulin or OAG treatment rapidly increased the superoxide generation through activation of NADH oxidase. TRPC inhibitor SKF96365 or siRNA knockdown of TRPC6 attenuated insulin-dependent increase of ROS production. Furthermore, TRPC inhibitor or downregulation of TRPC6 blocked insulin-induced rearrangement of the actin cytoskeleton and attenuated oxidative activation of PKGIα and changes in the phosphorylation of PKG target proteins MYPT1 and MLC. Moreover insulin regulated the PKGIα interaction with TRPC6 in cultured rat podocytes. Taken together, our data suggest a key role of TRPC6 channels in the mediation of insulin-dependent activation of PKGIα signaling pathways. Overall, we have identified a potentially important mechanism that may explain disturbances in filtration barrier permeability in many diseases with increased expression of TRPC6 and chronic Ca2+ overload.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
medicine.medical_treatment
Biology
Permeability
Podocyte
TRPC6
03 medical and health sciences
Downregulation and upregulation
Glomerular Filtration Barrier
Internal medicine
medicine
Animals
Insulin
Rats, Wistar
Molecular Biology
TRPC
Cyclic GMP-Dependent Protein Kinase Type I
TRPC Cation Channels
Imidazoles
Actin cytoskeleton
Cell biology
Rats
Enzyme Activation
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Molecular Medicine
Female
cGMP-dependent protein kinase
Signal Transduction
Subjects
Details
- ISSN :
- 09254439
- Volume :
- 1863
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Accession number :
- edsair.doi.dedup.....952ed4962b0a7c84e11f86df8a114eae