自噬与ADPKD
Autophagy and Autosomal Dominant Polycystic Kidney Disease

DOI: 10.12677/JPS.2015.34004, PP. 19-26

Keywords: 自噬，常染色体显性遗传多囊肾病，凋亡，mTOR，纤毛
Autophagy, Autosomal Dominant Polycystic Kidney Disease, Apoptosis, mTOR, Cilia

Full-Text   Cite this paper   Add to My Lib

Abstract:

自噬是胞质内成分被转运至溶酶体内降解为初级成分的过程，以维持细胞内稳态和能量产生，其三条通路包括巨自噬、分子伴侣介导的自噬和微自噬。自噬参与到某些肾脏疾病的病理过程中，如急性肾损伤、糖尿病肾病和常染色体显性遗传多囊肾病(autosomal dominant polycystic kidney disease, ADPKD)。ADPKD由Pkd1或Pkd2基因的突变引起，致使细胞内钙离子稳态失衡，进而导致肾囊泡的形成及生长。一些涉及囊泡生长的信号通路也参与自噬的调节，因此PKD的病理机制与自噬存在密切联系。本文主要对PKD与自噬的调节以及自噬与凋亡、mTOR信号通路及纤毛功能之间的关系等方面的研究进展进行综述。
Autophagy is the process that cytoplasmic components are transported into lysosomes and de-graded to primary components, maintaining the cellular homeostasis and energy production. The three pathways of autophagy include macroautophagy, chaperone-mediated autophagy, and microautophagy. Autophagy is involved in pathogenesis of several important renal diseases, such as acute kidney injury, diabetic nephropathy and autosomal dominant polycystic kidney disease (ADPKD). ADPKD is caused by mutations of Pkd1 or Pkd2, resulting in the imbalance of intracellular calcium and furthermore the formation and growth of cysts. Several pathways involved in cyst growth also play a role in autophagy, thus implying the association of pathogenesis of PKD and autophagy. Overall, we reviewed the suppressed autophagy in PKD, and the relation between autophagy and apoptosis, mTOR signaling pathway, and ciliary function in PKD.

References

[1]	Ravikumar, B., Sarkar, S., Davies, J.E., et al. (2010) Regulation of Mammalian Autophagy in Physiology and Pathophysiology. Physiological Reviews, 90, 1383-1435. http://dx.doi.org/10.1152/physrev.00030.2009
[2]	De Rechter, S., Decuypere, J., Ivanova, E., et al. (2015) Autophagy in Renal Diseases. Pediatric Nephrology, 1-16. http://dx.doi.org/10.1007/s00467-015-3134-2
[3]	Huber, T.B., Edelstein, C.L., Hartleben, B., et al. (2014) Emerging Role of Autophagy in Kidney Function, Diseases and Aging. Autophagy, 8, 1009-1031. http://dx.doi.org/10.4161/auto.19821
[4]	Hotchkiss, R.S., Strasser, A., Mcdunn, J.E., et al. (2009) Cell Death. New England Journal of Medicine, 361, 1570- 1583. http://dx.doi.org/10.1056/NEJMra0901217
[5]	Kaushik, S. and Cuervo, A.M. (2012) Chaperone-Mediated Autophagy: A Unique Way to Enter the Lysosome World. Trends in Cell Biology, 22, 407-417. http://dx.doi.org/10.1016/j.tcb.2012.05.006
[6]	Li, W.W., Li, J. and Bao, J.K. (2012) Microautophagy: Lesser-Known Self-Eating. Cellular and Molecular Life Sciences, 69, 1125-1136. http://dx.doi.org/10.1007/s00018-011-0865-5
[7]	Torres, V.E., Harris, P.C. and Pirson, Y. (2007) Autosomal Dominant Polycystic Kidney Disease. Lancet, 369, 1287- 1301. http://dx.doi.org/10.1016/S0140-6736(07)60601-1
[8]	Kotsis, F., Boehlke, C. and Kuehn, E.W. (2013) The Ciliary Flow Sensor and Polycystic Kidney Disease. Nephrology Dialysis Transplantation, 28, 518-526. http://dx.doi.org/10.1093/ndt/gfs524
[9]	Ko, J.Y. and Park, J.H. (2013) Mouse Models of Polycystic Kidney Disease Induced by Defects of Ciliaryproteins. BMB Reports, 46, 73-79. http://dx.doi.org/10.5483/BMBRep.2013.46.2.022
[10]	Ong, A.C., Devuyst, O., Knebelmann, B., et al. (2015) Autosomal Dominant Polycystic Kidney Disease: The Changing Face of Clinical Management. Lancet, 385, 1993-2002. http://dx.doi.org/10.1016/S0140-6736(15)60907-2
[11]	Ravichandran, K. and Edelstein, C.L. (2014) Polycystic Kidney Disease: A Case of Suppressed Autophagy? Seminars in Nephrology, 34, 27-33. http://dx.doi.org/10.1016/j.semnephrol.2013.11.005
[12]	Leuenroth, S.J., Bencivenga, N., Chahboune, H., et al. (2010) Triptolide Reduces Cyst Formation in a Neonatal to Adult Transition Pkd1 Model of ADPKD. Nephrology Dialysis Transplantation, 25, 2187-2194. http://dx.doi.org/10.1093/ndt/gfp777
[13]	Belibi, F., Zafar, I., Ravichandran, K., et al. (2011) Hypoxia-Inducible Factor-1 (HIF-1) and Autophagy in Polycystic Kidney Disease (PKD). AJP: Renal Physiology, 300, F1235-F1243. http://dx.doi.org/10.1152/ajprenal.00348.2010
[14]	Mizushima, N., Yoshimori, T. and Levine, B. (2010) Methods in Mammalian Autophagy Research. Cell, 140, 313-326. http://dx.doi.org/10.1016/j.cell.2010.01.028
[15]	Bellot, G., Garcia-Medina, R., Gounon, P., et al. (2009) Hypoxia-Induced Autophagy Is Mediated through Hypoxia- Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains. Molecular and Cellular Biology, 29, 2570- 2581. http://dx.doi.org/10.1128/MCB.00166-09
[16]	Bohensky, J., Shapiro, I.M., Leshinsky, S., et al. (2007) HIF-1 Regulation of Chondrocyte Apoptosis: Induction of the Autophagic Pathway. Autophagy, 3, 207-214. http://dx.doi.org/10.4161/auto.3708
[17]	Edelstein, C.L. (2005) What Is the Role of Tubular Epithelial Cell Apoptosis in Polycystic Kidney Disease (PKD)? Cell Cycle, 4, 1550-1554. http://dx.doi.org/10.4161/cc.4.11.2185
[18]	Tao, Y., Kim, J., Faubel, S., et al. (2005) Caspase Inhibition Reduces Tubular Apoptosis and Proliferation and Slows Disease Progression in Polycystic Kidney Disease. Proceedings of the National Academy of Sciences of the United States of America, 102, 6954-6959. http://dx.doi.org/10.1073/pnas.0408518102
[19]	Tao, Y., Zafar, I., Kim, J., et al. (2008) Caspase-3 Gene Deletion Prolongs Survival in Polycystic Kidney Disease. Journal of the American Society of Nephrology, 19, 749-755. http://dx.doi.org/10.1681/asn.2006121378
[20]	Veis, D.J, Sorenson, C.M., Shutter, J.R., et al. (1993) Bcl-2-Deficient Mice Demonstrate Fulminant Lymphoid Apoptosis, Polycystic Kidneys, and Hypopigmented Hair. Cell, 75, 229-240. http://dx.doi.org/10.1016/0092-8674(93)80065-M
[21]	Saeki, K., You, A., Okuma, E., et al. (2000) Bcl-2 Down-Regulation Causes Autophagy in a Caspase-Independent Manner in Human Leukemic HL60 Cells. Cell Death & Differentiation, 7, 1263-1269. http://dx.doi.org/10.1038/sj.cdd.4400759
[22]	Tsujimoto, Y. and Shimizu, S. (2005) Another Way to Die: Autophagic Programmed Cell Death. Cell Death & Differentiation, 12, 1528-1534. http://dx.doi.org/10.1038/sj.cdd.4401777
[23]	Lin, H.H., Yang, T.P., Jiang, S.T., et al. (1999) Bcl-2 Overexpression Prevents Apoptosis-Induced Madin-Darby Canine Kidney Simple Epithelial Cyst Formation. Kidney International, 55, 168-178. http://dx.doi.org/10.1046/j.1523-1755.1999.00249.x
[24]	Bukanov, N.O., Smith, L.A., Klinger, K.W., et al. (2006) Long-Lasting Arrest of Murine Polycystic Kidney Disease with CDK Inhibitor Roscovitine. Nature, 444, 949-952. http://dx.doi.org/10.1038/nature05348
[25]	Boletta, A., Qian, F., Onuchic, L.F., et al. (2000) Polycystin-1, the Gene Product of PKD1, Induces Resistance to Apoptosis and Spontaneous Tubulogenesis in MDCK Cells. Molecular Cell, 6, 1267-1273. http://dx.doi.org/10.1016/S1097-2765(00)00123-4
[26]	Rowe, I., Chiaravalli, M., Mannella, V., et al. (2013) Defective Glucose Metabolism in Polycystic Kidney Disease Identifies a New Therapeutic Strategy. Nature Medicine, 19, 488-493. http://dx.doi.org/10.1038/nm.3092
[27]	Zhou, F., Yang, Y. and Xing, D. (2011) Bcl-2 and Bcl-xL Play Important Roles in the Crosstalk between Autophagy and Apoptosis. FEBS Journal, 278, 403-413. http://dx.doi.org/10.1111/j.1742-4658.2010.07965.x
[28]	Yu, L., Alva, A., Su, H., et al. (2004) Regulation of an ATG7-Beclin 1 Program of Autophagic Cell Death by Caspase-8. Science, 304, 1500-1502. http://dx.doi.org/10.1126/science.1096645
[29]	Giansanti, V., Torriglia, A. and Scovassi, A.I. (2011) Conversation between Apoptosis and Autophagy: “Is It Your Turn or Mine?” Apoptosis, 16, 321-333. http://dx.doi.org/10.1007/s10495-011-0589-x
[30]	Kaushal, G.P., Kaushal, V., Herzog, C., et al. (2008) Autophagy Delays Apoptosis in Renal Tubular Epithelial Cells in Cisplatin Cytotoxicity. Autophagy, 4, 710-712. http://dx.doi.org/10.4161/auto.6309
[31]	Korolchuk, V.I. and Rubinsztein, D.C. (2011) Regulation of Autophagy by Lysosomal Positioning. Autophagy, 7, 927- 928. http://dx.doi.org/10.4161/auto.7.8.15862
[32]	Tao, Y., Kim, J., Schrier, R.W., et al. (2005) Rapamycin Markedly Slows Disease Progression in a Rat Model of Polycystic Kidney Disease. Journal of the American Society of Nephrology, 16, 46-51. http://dx.doi.org/10.1681/ASN.2004080660
[33]	Shillingford, J.M., Piontek, K.B., Germino, G.G., et al. (2010) Rapamycin Ameliorates PKD Resulting from Conditional Inactivation of Pkd1. Journal of the American Society of Nephrology, 21, 489-497. http://dx.doi.org/10.1681/asn.2009040421
[34]	Huber, T.B., Walz, G. and Kuehn, E.W. (2011) mTOR and Rapamycin in the Kidney: Signaling and Therapeutic Implications beyond Immunosuppression. Kidney International, 79, 502-511. http://dx.doi.org/10.1038/ki.2010.457
[35]	Zafar, I., Ravichandran, K., Belibi, F.A., et al. (2010) Sirolimus Attenuates Disease Progression in an Orthologous Mouse Model of Human Autosomal Dominant Polycystic Kidney Disease. Kidney International, 78, 754-761. http://dx.doi.org/10.1038/ki.2010.250
[36]	Natoli, T.A., Smith, L.A., Rogers, K.A., et al. (2010) Inhibition of Glucosylceramide Accumulation Results in Effective Blockade of Polycystic Kidney Disease in Mouse Models. Nature Medicine, 16, 788-792. http://dx.doi.org/10.1038/nm.2171
[37]	Walz, G., Budde, K., Mannaa, M., et al. (2010) Everolimus in Patients with Autosomal Dominant Polycystic Kidney Disease. The New England Journal of Medicine, 363, 830-840. http://dx.doi.org/10.1056/NEJMoa1003491
[38]	Belibi, F., Ravichandran, K., Zafar, I., et al. (2011) mTORC1/2 and Rapamycin in Female Han:SPRD Rats with Polycystic Kidney Disease. American Journal of Physiology—Renal Physiology, 300, F236-F244. http://dx.doi.org/10.1152/ajprenal.00129.2010
[39]	Chresta, C.M., Davies, B.R., Hickson, I., et al. (2010) AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP- Competitive Mammalian Target of Rapamycin Kinase Inhibitor with in Vitro and in Vivo Antitumor Activity. Cancer Research, 70, 288-298. http://dx.doi.org/10.1158/0008-5472.CAN-09-1751
[40]	Boehlke, C., Kotsis, F., Patel, V., et al. (2010) Primary Cilia Regulate mTORC1 Activity and Cell Size through Lkb1. Nature Cell Biology, 12, 1115-1122. http://dx.doi.org/10.1038/ncb2117
[41]	Pampliega, O., Orhon, I., Patel, B., et al. (2013) Functional Interaction between Autophagy and Ciliogenesis. Nature, 502, 194-200. http://dx.doi.org/10.1038/nature12639
[42]	Wang, S., Livingston, M.J., Su, Y., et al. (2015) Reciprocal Regulation of Cilia and Autophagy via the MTOR and Proteasome Pathways. Autophagy, 11, 607-616. http://dx.doi.org/10.1080/15548627.2015.1023983
[43]	Takakura, A., Nelson, E.A., Haque, N., et al. (2011) Pyrimethamine Inhibits Adult Polycystic Kidney Disease by Modulating STAT Signaling Pathways. Human Molecular Genetics, 20, 4143-4154. http://dx.doi.org/10.1093/hmg/ddr338
[44]	Yu, W., Kong, T., Beaudry, S., et al. (2010) Polycystin-1 Protein Level Determines Activity of the Galpha12/JNK Apoptosis Pathway. The Journal of Biological Chemistry, 285, 10243-10251. http://dx.doi.org/10.1074/jbc.M109.070821
[45]	Takiar, V., Nishio, S., Seo-Mayer, P., et al. (2011) Activating AMP-Activated Protein Kinase (AMPK) Slows Renal Cystogenesis. Proceedings of the National Academy of Sciences of the United States of America, 108, 2462-2467. http://dx.doi.org/10.1073/pnas.1011498108
[46]	Mccarty, M.F., Barroso-Aranda, J. and Contreras, F. (2009) Activation of AMP-Activated Kinase as a Strategy for Managing Autosomal Dominant Polycystic Kidney Disease. Medical Hypotheses, 73, 1008-1010. http://dx.doi.org/10.1016/j.mehy.2009.05.043
[47]	Cebotaru, V., Cebotaru, L., Kim, H., et al. (2014) Polycystin-1 Negatively Regulates Polycystin-2 Expression via the Aggresome/Autophagosome Pathway. Journal of Biological Chemistry, 289, 6404-6414. http://dx.doi.org/10.1074/jbc.M113.501205
[48]	Parkhitko, A., Myachina, F., Morrison, T.A., et al. (2011) Tumorigenesis in Tuberous Sclerosis Complex Is Autophagy and p62/Sequestosome 1 (SQSTM1)-Dependent. Proceedings of the National Academy of Sciences of the United States of America, 108, 12455-12460. http://dx.doi.org/10.1073/pnas.1104361108
[49]	Turcotte, S., Chan, D.A., Sutphin, P.D., et al. (2008) A Molecule Targeting VHL-Deficient Renal Cell Carcinoma That Induces Autophagy. Cancer Cell, 14, 90-102. http://dx.doi.org/10.1016/j.ccr.2008.06.004

Full-Text