The canonical transient receptor potential channel 6 (TRPC6) has been recently added to the growing number of genes involved in familial forms of proteinuric kidney disease, characterized by nephrosis and ultimate renal failure. Interestingly, all TRPC6 mutations known to date are gain of function mutations, suggesting that increased Ca+2 influx through TRPC6 channels leads to podocyte injury. The mechanisms for TRPC channel regulation in podocytes are largely unknown. Furthermore, the question remains whether an increase in Ca+2 influx through TRPC channels occurs in both genetic and acquired forms of proteinuric kidney disease. Our preliminary data suggest that TRPC1 and TRPC5 are expressed in glomerular podocytes, where, like TRPC6, they localize to podocyte foot processes, in the vicinity of slit diaphragms. Our adhesion assays and wound assays in podocytes demonstrate a striking translocation of channel to membrane ruffles, indicating that channel localization is a regulated process. Angiotensin induces prominent calcium transients in podocytes expressing the AT1R, and a significant portion of this calcium influx appears to be mediated by TRPC channels. Patch clamp experiments in podocytes confirm the presence of a TRPC-like current. Single channel recordings suggest that channel activity is regulated by channel translocation to the membrane. When membrane trafficking is disrupted by pharmacologic and molecular techniques in podocytes, the TRPC-like current is largely diminished, supporting the notion that channel activity is regulated by channel translocation to the membrane. Based on our preliminary work, we hypothesize that TRPC1 and TRPC5 form novel channels in podocytes, which, in concert with TRPC6, mediate Ca+2 influx by their regulated translocation to the plasma membrane in response to upstream signaling through the Angiotensin Type 1 Receptor.
This work on the role of TRPC channels in proteinuric kidney disease will help identify targets for the development of medications and therapies to treat and prevent diseases such as nephrotic syndrome and diabetic nephropathy, which currently affect many kidney disease patients worldwide.
| Christov, Marta; Clark, Abbe R; Corbin, Braden et al. (2018) Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities. JCI Insight 3: |
| Buvall, Lisa; Wallentin, Hanna; Sieber, Jonas et al. (2017) Synaptopodin Is a Coincidence Detector of Tyrosine versus Serine/Threonine Phosphorylation for the Modulation of Rho Protein Crosstalk in Podocytes. J Am Soc Nephrol 28:837-851 |
| Zhou, Yiming; Castonguay, Philip; Sidhom, Eriene-Heidi et al. (2017) A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science 358:1332-1336 |
| Greka, Anna; Weins, Astrid; Mundel, Peter (2014) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 370:1263-6 |
| Buvall, Lisa; Rashmi, Priyanka; Lopez-Rivera, Esther et al. (2013) Proteasomal degradation of Nck1 but not Nck2 regulates RhoA activation and actin dynamics. Nat Commun 4:2863 |
| Schaldecker, Thomas; Kim, Sookyung; Tarabanis, Constantine et al. (2013) Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest 123:5298-309 |
| Yu, Chih-Chuan; Fornoni, Alessia; Weins, Astrid et al. (2013) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 369:2416-23 |
| Carrasquillo, Robert; Tian, Dequan; Krishna, Sneha et al. (2012) SNF8, a member of the ESCRT-II complex, interacts with TRPC6 and enhances its channel activity. BMC Cell Biol 13:33 |
| Greka, Anna; Mundel, Peter (2012) Calcium regulates podocyte actin dynamics. Semin Nephrol 32:319-26 |
| Greka, Anna; Mundel, Peter (2012) Cell biology and pathology of podocytes. Annu Rev Physiol 74:299-323 |
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