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.
|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|
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|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|
|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|
|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|
|Adair, Brian D; Altintas, Mehmet M; MÃ¶ller, Clemens C et al. (2014) Structure of the kidney slit diaphragm adapter protein CD2-associated protein as determined with electron microscopy. J Am Soc Nephrol 25:1465-73|
|Tian, Xuefei; Kim, Jin Ju; Monkley, Susan M et al. (2014) Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance. J Clin Invest 124:1098-113|
|Trachtman, Howard; Reiser, Jochen (2014) suPAR is the circulating factor in some but not all FSGS. Nat Rev Nephrol 10:610|
|Fiorina, Paolo; Vergani, Andrea; Bassi, Roberto et al. (2014) Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol 25:1415-29|
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