Angiotensin II Contributes to Podocyte Injury by Increasing TRPC6 Expression via an NFAT-Mediated Positive Feedback Signaling Pathway
Tom Nijenhuis,Alexis Sloan,Joost G. J. Hoenderop,Jan Flesche,Harry van Goor,Andreas D. Kistler,Marinka A.H. Bakker,René J. M. Bindels,Rudolf A. de Boer,Clemens C. Möller,Inge Hamming,Gerjan Navis,Jack F.M. Wetzels,Jo H. M. Berden,Jochen Reiser,Christian Faul,Johan van der Vlag +16 more
Reads0
Chats0
TLDR
The findings demonstrate that the deleterious effects of AngII on podocytes and its pathogenic role in glomerular disease involve enhanced TRPC6 expression via a calcineurin/NFAT positive feedback signaling pathway.Abstract:
The transient receptor potential channel C6 (TRPC6) is a slit diaphragm-associated protein in podocytes involved in regulating glomerular filter function. Gain-of-function mutations in TRPC6 cause hereditary focal segmental glomerulosclerosis (FSGS), and several human acquired proteinuric diseases show increased glomerular TRPC6 expression. Angiotensin II (AngII) is a key contributor to glomerular disease and may regulate TRPC6 expression in nonrenal cells. We demonstrate that AngII regulates TRPC6 mRNA and protein levels in cultured podocytes and that AngII infusion enhances glomerular TRPC6 expression in vivo. In animal models for human FSGS (doxorubicin nephropathy) and increased renin-angiotensin system activity (Ren2 transgenic rats), glomerular TRPC6 expression was increased in an AngII-dependent manner. TRPC6 expression correlated with glomerular damage markers and glomerulosclerosis. We show that the regulation of TRPC6 expression by AngII and doxorubicin requires TRPC6-mediated Ca(2+) influx and the activation of the Ca(2+)-dependent protein phosphatase calcineurin and its substrate nuclear factor of activated T cells (NFAT). Accordingly, calcineurin inhibition by cyclosporine decreased TRPC6 expression and reduced proteinuria in doxorubicin nephropathy, whereas podocyte-specific inducible expression of a constitutively active NFAT mutant increased TRPC6 expression and induced severe proteinuria. Our findings demonstrate that the deleterious effects of AngII on podocytes and its pathogenic role in glomerular disease involve enhanced TRPC6 expression via a calcineurin/NFAT positive feedback signaling pathway.read more
Citations
More filters
Journal ArticleDOI
Cell Biology and Pathology of Podocytes
Anna Greka,Peter Mundel +1 more
TL;DR: A membrane biologist's view of the podocyte is taken, examining the many membrane receptors, channels, and other signaling molecules that have been implicated in podocyte biology and emphasizing that this approach may be fruitful in understanding the podocytes and its unique properties.
Journal ArticleDOI
Insulin increases surface expression of TRPC6 channels in podocytes: role of NADPH oxidases and reactive oxygen species.
TL;DR: It is shown that insulin increases generation of ROS in part through activation of NADPH oxidases, and that this step contributes to modulation of podocyte TRPC6 channels.
Journal ArticleDOI
Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury
Christopher E. Pedigo,Gloria Michelle Ducasa,Farah Leclercq,Alexis Sloan,Alla Mitrofanova,Tahreem Hashmi,Judith Molina-David,Mengyuan Ge,Mariann I. Lassenius,Carol Forsblom,Markku Lehto,Per-Henrik Groop,Per-Henrik Groop,Matthias Kretzler,Sean Eddy,Sebastian Martini,Heather N. Reich,Patricia Wahl,Gian Marco Ghiggeri,Christian Faul,George W. Burke,Oliver Kretz,Tobias B. Huber,Armando J. Mendez,Sandra Merscher,Alessia Fornoni +25 more
TL;DR: The data implicate an NFATc1/ABCA1-dependent mechanism in which local TNF is sufficient to cause free cholesterol-dependent podocyte injury irrespective of TNF, TNFR1, or TNFR2 serum levels.
Journal ArticleDOI
Childhood nephrotic syndrome—current and future therapies
TL;DR: This Review summarizes the currently available treatments for childhood nephrotic syndrome, and discusses selected novel pathways in podocytes that could be targeted for the development of next-generation treatments for children with this syndrome.
Journal ArticleDOI
MicroRNA-30 family members regulate calcium/calcineurin signaling in podocytes
Junnan Wu,Chunxia Zheng,Xiao Wang,Shifeng Yun,Yue Zhao,Lin Liu,Yuqiu Lu,Yuting Ye,Xiaodong Zhu,Changming Zhang,Shaolin Shi,Zhihong Liu +11 more
TL;DR: In this paper, the authors showed that miR-30s are essential regulators of calcium/calcineurin signaling in normal podocytes and patients with focal segmental glomerulosclerosis (FSGS).
References
More filters
Journal ArticleDOI
TRP channels as cellular sensors
TL;DR: TRP channels are the vanguard of the authors' sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli, but their role is much broader than classical sensory transduction.
Journal ArticleDOI
Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.
Thomas Hofmann,Alexander G. Obukhov,Michael Schaefer,Christian Harteneck,Thomas Gudermann,Günter Schultz +5 more
TL;DR: The molecular mechanism of store-depletion-independent activation of a subfamily of mammalian TRPC channels is described and it is found that hTRPC6 is a non-selective cation channel that is activated by diacylglycerol in a membrane-delimited fashion, independently of protein kinases C activated bydiacyl Glycerol.
Journal ArticleDOI
A Mutation in the TRPC6 Cation Channel Causes Familial Focal Segmental Glomerulosclerosis
Michelle P. Winn,Peter J. Conlon,Kelvin L. Lynn,Merry Kay Farrington,Tony Creazzo,April F. Hawkins,Nikki Daskalakis,Shu Ying Kwan,Seth M. Ebersviller,James L. Burchette,Margaret A. Pericak-Vance,David N. Howell,Jeffery M. Vance,Paul B. Rosenberg +13 more
TL;DR: In this article, a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6).
Journal ArticleDOI
Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria
Piero Ruggenenti,Annalisa Perna,Giulia Gherardi,Giovanni Garini,Carmine Zoccali,Maurizio Salvadori,Francesco Scolari,Francesco Paolo Schena,Giuseppe Remuzzi +8 more
TL;DR: In non-diabetic nephropathies, ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria, and the rate of decline in GFR and the frequency of ESRF were much lower in stratum 1 than they had been instratum 2.
Journal ArticleDOI
The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A
Christian Faul,Mary Donnelly,Mary Donnelly,Sandra Merscher-Gomez,Sandra Merscher-Gomez,Yoon Hee Chang,Yoon Hee Chang,Stefan Franz,Stefan Franz,Jacqueline Delfgaauw,Jacqueline Delfgaauw,Jer Ming Chang,Hoon Young Choi,Kirk N. Campbell,Kirk N. Campbell,Kwanghee Kim,Jochen Reiser,Jochen Reiser,Peter Mundel,Peter Mundel +19 more
TL;DR: It is shown that the beneficial effect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from the stabilization of the actin cytoskeleton in kidney podocytes, preserving the phosphorylation-dependent synaptopodin–14-3-3β interaction.
Related Papers (5)
TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.
The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A
Christian Faul,Mary Donnelly,Mary Donnelly,Sandra Merscher-Gomez,Sandra Merscher-Gomez,Yoon Hee Chang,Yoon Hee Chang,Stefan Franz,Stefan Franz,Jacqueline Delfgaauw,Jacqueline Delfgaauw,Jer Ming Chang,Hoon Young Choi,Kirk N. Campbell,Kirk N. Campbell,Kwanghee Kim,Jochen Reiser,Jochen Reiser,Peter Mundel,Peter Mundel +19 more