TRPC3 and TRPC6 Contribute to the Pathogenesis of Hypertension


Recently studies found that TRPC3 and TRPC6 played an important role in cardiovascular disease. Hypertension, as a cardiovascular disease causing the highest morbidity and mortality, has close relationship with the expressions of TRPC3 and TRPC6. Unbalanced calcium homeostasis is the major factor of pathogenesis of hypertension. Changes of intracellular calcium concentration depend on calcium transmembrane transportation, intracellular calcium store releasing and other processes. TRPC3, TRPC6 molecules, as non-selective cation channels on the cell membranes, are involved in the processes. This review illustrated the functions of TRPC3 and TRPC6 on myocardial cells, smooth muscle cells and inflammatory cells in the development of hypertension, and the effects of drugs like sildenafil to provide a new way for the prevention and treatment of hypertension.

Share and Cite:

Zou, Q. , Zhang, C. and Guo, Y. (2015) TRPC3 and TRPC6 Contribute to the Pathogenesis of Hypertension. American Journal of Molecular Biology, 5, 124-133. doi: 10.4236/ajmb.2015.54011.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Dietrich, A., Kalwa, H. and Gudermann, T. (2010) TRPC Channels in Vascular Cell Function. Thrombosis and Haemostasis, 103, 262-270.
[2] Rowell, J., Koitabashi, N. and Kass, D.A. (2010) TRP-ing up Heart and Vessels: Canonical Transient Receptor Potential Channels and Cardiovascular Disease. Journal of Cardiovascular Translational Research, 5, 516-524.
[3] Trebak, M. (2010) The Puzzling Role of TRPC3 Channels in Motor Coordination. Pflügers Archiv, 459, 369-375.
[4] Dryer, S.E. and Reiser, J. (2010) TRPC6 Channels and Their Binding Partners in Podocytes: Role in Glomerular Filtration and Pathophysiology. American Journal of Physiology, 299, F689-701.
[5] Yuan, J.P., Kim, M.S., Zeng, W., Shin, D.M., Huang, G. and Worley, P.F. (2009) TRPC Channels as STIM1-Regulated SOCs. Channels (Austin), 3, 221-225.
[6] Doleschal, B., Primessnig, U., Wölkart, G., Wolf, S., Schernthaner, M., Lichtenegger, M., et al. (2015) TRPC3 Contributes to Regulation of Cardiac Contractility and Arrhythmogenesis by Dynamic Interaction with NCX1. Cardiovascular Research, 106, 163-173.
[7] Meng, K., Xu, J., Zhang, C., Zhang, R., Yang, H., Liao, C. and Jiao, J. (2014) Calcium Sensing Receptor Modulates Extracellular Calcium Entry and Proliferation via TRPC3/6 Channels in Cultured Human Mesangial Cells. PLoS One, 9, e98777.
[8] Okamoto, K. and Aoki, K. (1963) Development of a Strain of Spontaneously Hypertensive rats. Japanese Circulation Journal, 27, 282-293.
[9] Liu, D., Scholze, A., Zhu, Z., Kreutz, R., Wehland-von-Trebra, M., Zidek, W., et al. (2005) Increased Transient Receptor Potential Channel TRPC3 Expression in Spontaneously Hypertensive rats. American Journal of Hypertension, 18, 1503-1507.
[10] Chen, X.P., Yang, D.C., Ma, S.T., He, H., Luo, Z. and Feng, X. (2010) Increased Rhythmicity in Hypertensive Arterial Smooth Muscle Is Linked to Transient Receptor Potential Canonical Channels. Journal of Cellular and Molecular Medicine, 14, 2483-2494.
[11] Wu, Y. (2013) The Effect of TRPC6 on Left Ventricular Hypertrophy in SHR—The Study of the Relationship between TRPC6 and BNP. Fujian Medical University, Fuzhou.
[12] Lin, X.H., Hong, H.S., Zou, G.R. and Chen, L.L. (2015) Upregulation of TRPC1/6 May Be Involved in Arterial Remodeling in Rat. Journal of Surgical Research, 195, 334-343.
[13] Wang, J., Chen, Y., Lin, C., Jia, J., Tian, L. and Yang, K. (2014) Effects of Chronic Exposure to Cigarette Smoke on Canonical Transient Receptor Potential Expression in Rat Pulmonary Arterial Smooth Muscle. AJP: Cell Physiology, 306, C364-C373.
[14] Liu, D., Scholze, A., Zhu, Z., Krueger, K., Thilo, F. and Burkert, A. (2006) Transient Receptor Potential Channels in Essential Hypertension. Hypertension, 24, 1105-1114.
[15] Zhao, Z., Ni, Y., Chen, J., Zhong, J., Yu, H. and Xu, X. (2012) Increased Migration of Monocytes in Essential Hypertension Is Associated with Increased Transient Receptor Potential Channel Canonical Type 3 Channels. PLoS ONE, 7, e32628.
[16] Liu, D.Y., Thilo, F., Scholze, A., Wittstock, A., Zhao, Z.G. and Harteneck, C. (2007) Increased Store-Operated and 1-Oleoyl-2-acetyl-sn-glycerol-Induced Calcium Influx in Monocytes Is Mediated by Transient Receptor Potential Canonical Channels in Human Essential Hypertension. Journal of Hypertension, 25, 799-808.
[17] Imai, Y., Itsuki, K., Okamura, Y., Inoue, R. and Mori, M.X. (2012) A Self-Limiting Regulation of Vasoconstrictor-Activated TRPC3/C6/C7 Channels Coupled to PI(4,5)P2-Diacylglycerol Signaling. The Journal of Physiology, 590, 1101-1119.
[18] Itsuki, K., Imai, Y., Hase, H., Okamura, Y., Inoue, R. and Mori, M.X. (2014) PLC-Mediated PI(4,5) P2 Hydrolysis Regulates Activation and Inactivation of TRPC6/7 Channels. The Journal of General Physiology, 143, 183-201.
[19] Adebiyi, A., Thomas-Gatewood, C.M., Leo, M.D., Kidd, M.W., Neeb, Z.P. and Jaggar, J.H. (2012) An Elevation in Physical Coupling of Type 1 IP3 Receptors to TRPC3 Channels Constricts Mesenteric Arteries in Genetic Hypertension. Hypertension, 60, 1213-1219.
[20] Xie, J., Cha, S.K., An, S.W., Kuro-O, M., Birnbaumer, L. and Huang, C.L. (2012) Cardioprotection by Klotho through Downregulation of TRPC6 Channels in the Mouse Heart. Nature Communications, 3, 1238.
[21] Chu, W., Wan, L., Zhao, D., Qu, X., Cai, F. and Huo, R. (2012) Mild Hypoxia-Induced Cardiomyocyte Hypertrophy via Up-Regulation of HIF-1α-Mediated TRPC Signaling. Journal of Cellular and Molecular Medicine, 16, 2022-2034.
[22] Catherine, A.M., Hong, Y.Z., Jennifer, D., Robert, N.C., Danielle, M.T., Nicholas, E.H., et al. (2014) Transient Receptor Potential Channels Contribute to Pathological Structural and Functional Remodeling after Myocardial Infarction. Circulation Research, 115, 567-580.
[23] Yue, Z., Zhang, Y., Xie, J., Jiang, J. and Yue, L. (2013) Transient Receptor Potential (TRP) Channels and Cardiac Fibrosis. Current Topics in Medicinal Chemistry, 13, 270-282.
[24] Davis, J., Burr, A.R., Davis, G.F., Birnbaumer, L. and Molkentin, J.D. (2012) A TRPC6-Dependent Pathway for Myofibroblast Transdifferentiation and Wound Healing in Vivo. Developmental Cell, 23, 705-715.
[25] Nakayama, H., Wilkin, B.J., Bodi, I. and Molkentin, J.D. (2006) Calcineurin-Dependent Cardiomyopathy Is Activated by TRPC in the Adult Mouse Heart. The FASEB Journal, 20, 1660-1670.
[26] Koichiro, K., Yanggan, W., John, M.A., James, A.R., Rhonda, B.D., Joseph, A.H., et al. (2006) TRPC6 Fulfills a Calcineurin Signaling Circuit during Pathologic Cardiac Remodeling. Journal of Clinical Investigation, 116, 3114-3126.
[27] Goulopoulou, S. and Webb, R.C. (2014) Symphony of Vascular Contraction: How Smooth Muscle Cells Lose Harmony to Signal Increased Vascular Resistance in Hypertension. Hypertension, 63, e33-e39.
[28] Noorani, M.M., Noel, R.C. and Marrelli, S.P. (2011) Up-Regulated TRPC3 and Down-Regulated TRPC1 Channel Expression during Hypertension Is Associated with Increased Vascular Contractility in Rat. Frontiers in Physiology, 2, 1-8.
[29] Xia, Y., Yang, X.R., Fu, Z., Paudel, O., Abramowitz, J. and Birnbaumer, L. (2014) Classical Transient Receptor Potential 1 and 6 Contribute to Hypoxic Pulmonary Hypertension through Differential Regulation of Pulmonary Vascular Functions. Hypertension, 63, 173-180.
[30] Zhang, Y., Lu, W., Yang, K., Xu, L., Lai, N. and Tian, L. (2013) Bone Morphogenetic Protein 2 Decreases TRPC Expression, Store-Operated Ca2+ Entry, and Basal [Ca2+]i in Rat Distal Pulmonary Arterial Smooth Muscle Cells. AJP: Cell Physiology, 304, C833-C843.
[31] Lin, M.J., Leung, G.P., Zhang, W.M., Yang, X.R., Yip, K.P. and Tse, C.M. (2004) Chronic Hypoxia-Induced Upregulation of Store-Operated and Receptor-Operated Ca2+ Channels in Pulmonary Arterial Smooth Muscle Cells: A Novel Mechanism of Hypoxic Pulmonary Hypertension. Circulation Research, 95, 496-505.
[32] Xu, L., Chen, Y., Yang, K., Wang, Y., Tian, L., Zhang, J., et al. (2014) Chronic Hypoxia Increases TRPC6 Expression and Basal Intracellular Ca2+ Concentration in Rat Distal Pulmonary Venous Smooth Muscle. PLoS ONE, 9, e112007.
[33] Wang, X.C., Li, M.X., Dang, X.Y., Li, P., Peng, Z. and Gao, Y.X. (2013) Calcineurin and TRPC6 Are Involved in ET-1-Induced Proliferation of Pulmonary Artery Smooth Muscle Cells. Acta Universitatis Medicinalis Nanjing (Natural Science), 33, 1191-1195.
[34] Liu, D., Yang, D., He, H., Chen, X., Cao, T. and Feng, X. (2009) Increased Transient Receptor Potential Canonical Type 3 Channels in Vasculature from Hypertensive Rats. Hypertension, 53, 70-76.
[35] Marvar, P.J., Vinh, A., Thabet, S., Lob, H.E., Geem, D., Ressler, K.J. and Harrison, D.G. (2012) T Lymphocytes and Vascular Inflammation Contribute to Stress-Dependent Hypertension. Biological Psychiatry, 71, 774-782.
[36] Thilo, F., Scholze, A., Liu, D.Y., Zidek, W. and Tepel, M. (2008) Association of Transient Receptor Potential Canonical Type 3 (TRPC3) Channel Transcripts with Proinflammatory Cytokines. Archives of Biochemistry and Biophysics, 471, 57-62.
[37] Wuensch, T., Thilo, F., Krueger, K., Scholze, A., Ristow, M. and Tepel, M. (2010) High Glucose-Induced Oxidative Stress Increases Transient Receptor Potential Channel Expression in Human Monocytes. Diabetes, 59, 844-849.
[38] Sanchez, M.E., Ibarra, S.A. and Gonzalez, E.C. (2010) Fyn Kinase Controls FcεRI Receptor-Operated Calcium Entry Necessary for Full Degranulation in Mast Cells. Biochemical and Biophysical Research Communications, 391, 1714-1720.
[39] Vig, M. and Kinet, J.-P. (2009) Calcium Signaling in Immune Cells. Nature Immunology, 10, 21-27.
[40] Harteneck, C. and Gollasch, M. (2011) Pharmacological Modulation of Diacylglycerol-Sensitive TRPC3/6/7 Channels. Current Pharmaceutical Biotechnology, 12, 35-41.
[41] Kim, M.S., Lee, K.P., Yang, D., Shin, D.M., Abramowitz, J., Kiyonaka, S., et al. (2011) Genetic and Pharmacologic Inhibition of the Ca2+ Influx Channel TRPC3 Protects Secretory Epithelia from Ca2+-Dependent Toxicity. Gastroenterology, 140, 2107-2115.
[42] Seo, K., Rainer, P.P., Shalkey, H.V., Lee, D.I., Jo, S.H. and Andersen, A. (2014) Combined TRPC3 and TRPC6 Blockade by Selective Small-Molecule or Genetic Deletion Inhibits Pathological Cardiac Hypertrophy. Proceedings of the National Academy of Sciences of the United States of America, 111, 1551-1556.
[43] Koitabashi, N., Aiba, T., Hesketh, G.G., Rowell, J., Zhang, M., Takimoto, E., et al. (2009) Cyclic GMP/PKG-Dependent Inhibition of TRPC6 Channel Activity and Expression Negatively Regulates Cardiomyocyte NFAT Activation Novel Mechanism of Cardiac Stress Modulation by PDE5 Inhibition. Journal of Molecular and Cellular Cardiology, 48, 713-724.
[44] Kiso, H., Ohba, T., Iino, K., Sato, K., Terata, Y. and Murakami, M. (2013) Sildenafil Prevents the Up-Regulation of Transient Receptor Potential Canonical Channels in the Development of Cardiomyocyte Hypertrophy. Biochemical and Biophysical Research Communications, 436, 514-518.
[45] Wang, J., Yang, K., Xu, L., Zhang, Y., Lai, N. and Jiang, H. (2013) Sildenafil Inhibits Hypoxia-Induced Transient Receptor Potential Canonical Protein Expression in Pulmonary Arterial Smooth Muscle via cGMP-PKG-PPARγ Axis. American Journal of Respiratory Cell and Molecular Biology, 49, 231-240.
[46] Liao, X.Y., Chen, M. and Yu, D.M. (2011) Effect of Anti-Hypertensive Medication on Expression of TRPC3 and TRPC6 in the Aorta of Spontaneous Hypertensive Rats. Chinese Circulation Journal, 26, 65-68.
[47] Yu, D.M., Chen, M. and Liao, X.Y. (2011) Effects of Antihypertensive Drugs on Expression of TRPC3 and TRPC6 in Left Ventricle of Spontaneously Hypertensive rats. International Journal of Cardiology, 152, S53.
[48] Toth, P., Tucsek, Z., Sosnowska, D., Gautam, T., Mitschelen, M. and Tarantini, S. (2013) Age-Related Autoregulatory Dysfunction and Cerebromicrovascular Injury in Mice with Angiotensin II-Induced Hypertension. Journal of Cerebral Blood Flow & Metabolism, 33, 1732-1742.
[49] Naoya, O., Motohiro, N., Ryuji, I., Kobayashi, H., Sumimoto, H. and Sato, Y. (2006) TRPC3 and TRPC6 Are Essential for Angiotensin II-Induced Cardiac Hypertrophy. The EMBO Journal, 25, 5305-5316.
[50] Nijenhuis, T., Sloan, A.J., Hoenderop, J.G., Flesche, J., Goor, H. and Kistler, A.D. (2011) Angiotensin II Contributes to Podocyte Injury by Increasing TRPC6 Expression via an NFAT-Mediated Positive Feed-Back Signaling Pathway. The American Journal of Pathology, 179, 1719-1732.

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.