This project aims to delineate disease causing mechanisms of dysfunctional ion channel TRPC6 in podocytes. TRPC6 is part of the slit diaphragm relating Ca2+ signals into podocyte foot processes and mutated TRPC6 or induced expression of wild type TRPC6 protein can cause hereditary and acquired proteinuric diseases, respectively. Thus, (dys-) regulation of TRPC6 likely affects millions of patients with glomerular disease. We have generated novel preliminary data demonstrating a unique functional interaction between TRPC6 and synaptopodin producing a regulatory loop, that coordinates physiological podocyte function but triggers podocyte injury in the case of dysregulated TRPC6 mediated Ca2+ signals. We propose to test our central hypothesis that TRPC6 and synaptopodin cooperate in the regulation of the dynamic podocyte actin cytoskeleton. While synaptopodin binds to TRPC6 and regulates its membrane expression, TRPC6 mediated Ca2+ influx determines the stability of synaptopodin through Ca2+ sensitive enzymes calcineurin and protein kinase A (PKA). According to our novel data, increased TRPC6 channel activity disrupts normal podocyte actin cytoskeletal dynamics via the activation of calcineurin that in turn leads to the degradation of synaptopodin thereby causing proteinuric kidney disease. In addition, diminished TRPC6 mediated Ca2+ influx into podocytes leads to reduced activity of PKA and thus reduced protective synaptopodin phosphorylation with its subsequent degradation. Normal Ca2+ transport of TRPC6 maintains physiological synaptopodin levels that allow a dynamic regulation of the podocyte foot process system and kidney barrier.
Specific Aim 1 will address how TRPC6 regulates synaptopodin-mediated actin cytoskeletal dynamics.
Specific Aim 2 seeks to define how synaptopodin affects TRPC6 channel activity and localization.
In Specific Aim 3, we will study the consequences of TRPC6 deficiency and TRPC6 hyperactivity on podocyte actin cytoskeletal dynamics and glomerular barrier function in vivo. Our work will clarify an important downstream mechanism that permits podocyte injury originating from dysregulated TRPC6. Our findings may have broad implications for the understanding of the pathobiology of TRPC6-related human kidney diseases including Focal Segmental Glomerulosclerosis (FSGS) and promote the development of anti-proteinuric drugs interfering with TRPC6 and its cellular effects on podocytes.
The broad, long-term goal of this grant proposal is to advance our understanding of podocyte biology and the molecular mechanisms leading to proteinuria and nephrotic syndrome that originate from podocyte injury. If our hypothesis is correct, our work may have broad implications for the understanding of the pathobiology of TRPC6-related human kidney diseases including Focal Segmental Glomerulosclerosis (FSGS) and promote the development of anti-proteinuric drugs interfering with TRPC6 channel function.
|Reiser, Jochen; Lee, Ha Won; Gupta, Vineet et al. (2017) A High-Content Screening Technology for Quantitatively Studying Podocyte Dynamics. Adv Chronic Kidney Dis 24:183-188|
|Yu, Hao; Kistler, Andreas; Faridi, Mohd Hafeez et al. (2016) Synaptopodin Limits TRPC6 Podocyte Surface Expression and Attenuates Proteinuria. J Am Soc Nephrol 27:3308-3319|
|Garin, Eduardo H; Reiser, Jochen; Cara-Fuentes, Gabriel et al. (2015) Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. Pediatr Nephrol 30:469-77|
|Lee, Ha Won; Khan, Samia Q; Faridi, Mohd Hafeez et al. (2015) A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules. J Am Soc Nephrol 26:2741-52|
|Li, Min; Armelloni, Silvia; Zennaro, Cristina et al. (2015) BDNF repairs podocyte damage by microRNA-mediated increase of actin polymerization. J Pathol 235:731-44|
|Yoo, Tae-Hyun; Pedigo, Christopher E; Guzman, Johanna et al. (2015) Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease. J Am Soc Nephrol 26:133-47|
|Anwar, Siddiq; Larson, Derek S; Naimi, Nima et al. (2015) A case report of adrenocorticotropic hormone to treat recurrent focal segmental glomerular sclerosis post-transplantation and biomarker monitoring. Front Med (Lausanne) 2:13|
|Cara-Fuentes, Gabriel; Wei, Changli; Segarra, Alfons et al. (2014) CD80 and suPAR in patients with minimal change disease and focal segmental glomerulosclerosis: diagnostic and pathogenic significance. Pediatr Nephrol 29:1363-71|
|Delville, Marianne; Sigdel, Tara K; Wei, Changli et al. (2014) A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med 6:256ra136|
|Reiser, Jochen; Sever, Sanja; Faul, Christian (2014) Signal transduction in podocytes--spotlight on receptor tyrosine kinases. Nat Rev Nephrol 10:104-15|
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