多囊腎疾病(Polycystic kidney disease, PKD)為最常見的遺傳疾病之一，盛行率高達1:400~1:1000，患者主要病徵為其腎元中各個部位發展出許多充滿液體的囊泡(cysts)構造。自體顯性多囊腎疾病(Autosomal dominant polycystic kidney disease; 簡稱ADPKD)為多囊腎疾病中最常見的類型，由PKD1 (佔其中85%)或PKD2 (佔其中15%)基因發生突變所導致。PKD1與PKD2分別表現polycystin-1 (PC1)與 polycystin-2 (PC2)蛋白，而PC1或PC2的功能缺損造成腎臟上皮細胞之不正常增殖，並進而導致囊泡形成。隨著ADPKD的進程，囊泡體積增加並破壞正常腎臟組織的結構，進而造成腎功能損傷，最終導致患者之腎臟衰竭。我們先前的研究建立了ADPKD之疾病模式鼠(Pkd1L3/L3小鼠)，並利用基因轉殖技術使病鼠在腎臟中大量表現外源性neutrophil nelatinase-associated lipocalin (Ngal)，結果顯示能夠減緩囊泡的進程並延長病鼠的壽命。Ngal是一22-kD之分泌性蛋白，尿液中之Ngal含量常用作檢測患者是否具有腎臟疾病的指標，而文獻中指出Ngal與其受器Ngal receptor (Ngal-R)之交互作用與細胞內鐵離子運輸有關，並能進一步誘導細胞凋亡(apoptosis)。然而，Ngal在ADPKD中之作用機制仍未知，如用動物模式(in vivo)進行研究有許多困難，如細胞間複雜之交互作用以及研究費時等，因此在本研究中建立3D細胞平台，並直接利用ADPKD疾病細胞模式(Pkd1L3/L3)進行Ngal蛋白之作用機制研究。細胞存活實驗(MTT)與細胞增殖實驗(BrdU incorporation)之結果顯示小鼠Ngal重組蛋白(mNgal)顯著降低ADPKD細胞模式之細胞活性與增殖，並顯著地抑制囊泡生長。根據流式細胞儀分析(flow cytometry)與西方墨點法(western blot)結果顯示，小鼠Ngal重組蛋白顯著抑制ADPKD細胞中ERK與AKT訊息傳遞路徑並誘導細胞凋亡與細胞自噬(autophagy)。再者，於ADPKD細胞中大量表現分泌性小鼠Ngal蛋白顯著抑制細胞增殖與囊泡生長，但大量表現非分泌性小鼠Ngal蛋白則不具有相同之抑制效果；這些結果表示Ngal需要從ADPKD細胞中被分泌出，才能抑制細胞增殖。未來我們將利用CRISPR技術將疾病細胞之Ngal-R基因剃除，進一步探討Ngal與Ngal-R在ADPKD中之作用機制。希望有助於了解Ngal在ADPKD細胞中之治療效果與機制。

Polycystic kidney disease (PKD), one of the most common inherited diseases with a prevalence of 1:400 to 1:1000, is characterized by the development of fluid-filled cysts along multiple segments of the nephron. Autosomal dominant polycystic kidney disease (ADPKD), the most common form of PKD, is the result of mutations in either PKD1 (85%) or PKD2 (15%) genes that encode polycystin-1 (PC1) and polycystin-2 (PC2) respectively. PC1 or PC2 defect is associated with abnormal increase in proliferation of renal epithelial cells and further causes cyst formation. As ADPKD progresses, cysts enlarge and disrupt the normal kidney construction, eventually leading to kidney failure. Our previous study has showed that overexpression of exogenous kidney-specific neutrophil gelatinase-associated lipocalin (Ngal), a 22-kD secreted protein and biomarker for kidney injuries, reduced cysts progression and prolonged the lifespan of ADPKD mice (Pkd1L3/L3, 2L3 for short). It has been demonstrated that Ngal and Ngal receptor (Ngal-R) coupling could sequester intracellular iron and further induce apoptosis. However, the mechanism of effects of Ngal in ADPKD is still unclear and having multiple difficulties studying in vivo, including complex cellular interaction systems and time consuming. In this study, results of MTT assay and BrdU incorporation assay showed that recombinant mouse Ngal (mNgal) protein significantly decreased cell viability and proliferation of 2L3 cells. Results of flow cytometry analysis and western blot showed that mNgal inhibited activation of ERK and AKT pathways and induced apoptosis and autophagy in 2L3 cells. In addition, 3D cell culture platform was established for testing the cyst progression of 2L3 renal epithelial cells, which showed that mNgal significantly inhibited cyst enlargement of 2L3 cells. Overexpression of secreted mNgal (pN+LS) rather than non-secreted mNgal (pN-LS) inhibited cell proliferation and cyst enlargement in 2L3 cells through inhibiting ERK and AKT pathways and inducing apoptosis and autophagy. These results reveal that secretion of mNgal from 2L3 cells is required to inhibit cell proliferation and cyst enlargement. To research the relationship between apoptosis and coupling of Ngal and Ngal-R in ADPKD cells, knockout of Ngal-R by CRISPR in 2L3 cells is being performed. We hope to identify the therapeutic effect and mechanism of Ngal protein on ADPKD cells.

An, S., X. Zang, W. Yuan, Y. Zhuge, and Q. Yu. 2013. 'Neutrophil gelatinase-associated lipocalin (NGAL) may play a protective role against rats ischemia/reperfusion renal injury via inhibiting tubular epithelial cell apoptosis', Ren Fail, 35: 143-9.
Bae, K., B. Park, H. Sun, J. Wang, C. Tao, A. B. Chapman, V. E. Torres, J. J. Grantham, M. Mrug, W. M. Bennett, M. F. Flessner, D. P. Landsittel, K. T. Bae, and Disease Consortium for Radiologic Imaging Studies of Polycystic Kidney. 2013. 'Segmentation of individual renal cysts from MR images in patients with autosomal dominant polycystic kidney disease', Clin J Am Soc Nephrol, 8: 1089-97.
Bao, Q., and R. C. Hughes. 1995. 'Galectin-3 expression and effects on cyst enlargement and tubulogenesis in kidney epithelial MDCK cells cultured in three-dimensional matrices in vitro', J Cell Sci, 108 ( Pt 8): 2791-800.
Bergmann, C. 2015. 'ARPKD and early manifestations of ADPKD: the original polycystic kidney disease and phenocopies', Pediatr Nephrol, 30: 15-30.
Bergmann, C., L. M. Guay-Woodford, P. C. Harris, S. Horie, D. J. M. Peters, and V. E. Torres. 2018. 'Polycystic kidney disease', Nat Rev Dis Primers, 4: 50.
Booij, T. H., H. Bange, W. N. Leonhard, K. Yan, M. Fokkelman, S. J. Kunnen, J. G. Dauwerse, Y. Qin, B. van de Water, G. J. P. van Westen, D. J. M. Peters, and L. S. Price. 2017. 'High-Throughput Phenotypic Screening of Kinase Inhibitors to Identify Drug Targets for Polycystic Kidney Disease', SLAS Discov, 22: 974-84.
Candido, S., S. L. Abrams, L. S. Steelman, K. Lertpiriyapong, T. L. Fitzgerald, A. M. Martelli, L. Cocco, G. Montalto, M. Cervello, J. Polesel, M. Libra, and J. A. McCubrey. 2016. 'Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy', Biochim Biophys Acta, 1863: 438-48.
Carlezon, W. A., Jr., R. S. Duman, and E. J. Nestler. 2005. 'The many faces of CREB', Trends Neurosci, 28: 436-45.
Chapman, A. B., O. Devuyst, K. U. Eckardt, R. T. Gansevoort, T. Harris, S. Horie, B. L. Kasiske, D. Odland, Y. Pei, R. D. Perrone, Y. Pirson, R. W. Schrier, R. Torra, V. E. Torres, T. Watnick, D. C. Wheeler, and Participants Conference. 2015. 'Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference', Kidney Int, 88: 17-27.
Chun, Y., and J. Kim. 2018. 'Autophagy: An Essential Degradation Program for Cellular Homeostasis and Life', Cells, 7.
Dalgaard, O. Z. 1957. 'Bilateral polycystic disease of the kidneys; a follow-up of two hundred and eighty-four patients and their families', Acta Med Scand Suppl, 328: 1-255.
Delmas, P., H. Nomura, X. Li, M. Lakkis, Y. Luo, Y. Segal, J. M. Fernandez-Fernandez, P. Harris, A. M. Frischauf, D. A. Brown, and J. Zhou. 2002. 'Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2', J Biol Chem, 277: 11276-83.
DesRochers, T. M., L. Suter, A. Roth, and D. L. Kaplan. 2013. 'Bioengineered 3D human kidney tissue, a platform for the determination of nephrotoxicity', PLoS One, 8: e59219.
Eccles, Michael R., and Cherie A. Stayner. 2014. 'Polycystic kidney disease - where gene dosage counts', F1000prime reports, 6: 24-24.
Elmore, S. 2007. 'Apoptosis: a review of programmed cell death', Toxicol Pathol, 35: 495-516.
Gattone, V. H., 2nd, X. Wang, P. C. Harris, and V. E. Torres. 2003. 'Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist', Nat Med, 9: 1323-6.
Goetz, D. H., M. A. Holmes, N. Borregaard, M. E. Bluhm, K. N. Raymond, and R. K. Strong. 2002. 'The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition', Mol Cell, 10: 1033-43.
Goggolidou, Paraskevi. 2014. 'Wnt and planar cell polarity signaling in cystic renal disease', Organogenesis, 10: 86-95.
Grantham, J. J. 2008. 'Clinical practice. Autosomal dominant polycystic kidney disease', N Engl J Med, 359: 1477-85.
Grantham, J. J., S. Mulamalla, and K. I. Swenson-Fields. 2011. 'Why kidneys fail in autosomal dominant polycystic kidney disease', Nat Rev Nephrol, 7: 556-66.
Hanaoka, K., O. Devuyst, E. M. Schwiebert, P. D. Wilson, and W. B. Guggino. 1996. 'A role for CFTR in human autosomal dominant polycystic kidney disease', Am J Physiol, 270: C389-99.
Hanaoka, K., and W. B. Guggino. 2000. 'cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells', J Am Soc Nephrol, 11: 1179-87.
Hanaoka, K., F. Qian, A. Boletta, A. K. Bhunia, K. Piontek, L. Tsiokas, V. P. Sukhatme, W. B. Guggino, and G. G. Germino. 2000. 'Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents', Nature, 408: 990-4.
Harris, P. C., K. T. Bae, S. Rossetti, V. E. Torres, J. J. Grantham, A. B. Chapman, L. M. Guay-Woodford, B. F. King, L. H. Wetzel, D. A. Baumgarten, P. J. Kenney, M. Consugar, S. Klahr, W. M. Bennett, C. M. Meyers, Q. J. Zhang, P. A. Thompson, F. Zhu, and J. P. Miller. 2006. 'Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease', J Am Soc Nephrol, 17: 3013-9.
Harris, P. C., and V. E. Torres. 2014. 'Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease', J Clin Invest, 124: 2315-24.
Igarashi, P., and S. Somlo. 2002. 'Genetics and pathogenesis of polycystic kidney disease', J Am Soc Nephrol, 13: 2384-98.
Jiang, S. T., Y. Y. Chiou, E. Wang, H. K. Lin, Y. T. Lin, Y. C. Chi, C. K. Wang, M. J. Tang, and H. Li. 2006. 'Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1', Am J Pathol, 168: 205-20.
Kabeya, Y., N. Mizushima, T. Ueno, A. Yamamoto, T. Kirisako, T. Noda, E. Kominami, Y. Ohsumi, and T. Yoshimori. 2000. 'LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing', EMBO J, 19: 5720-8.
Kawano, H., S. Muto, Y. Ohmoto, F. Iwata, H. Fujiki, T. Mori, L. Yan, and S. Horie. 2015. 'Exploring urinary biomarkers in autosomal dominant polycystic kidney disease', Clin Exp Nephrol, 19: 968-73.
Koptides, M., R. Mean, K. Demetriou, A. Pierides, and C. C. Deltas. 2000. 'Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal dominant polycystic kidney disease', Hum Mol Genet, 9: 447-52.
Langelueddecke, C., E. Roussa, R. A. Fenton, N. A. Wolff, W. K. Lee, and F. Thevenod. 2012. 'Lipocalin-2 (24p3/neutrophil gelatinase-associated lipocalin (NGAL)) receptor is expressed in distal nephron and mediates protein endocytosis', J Biol Chem, 287: 159-69.
Lee, G. Y., P. A. Kenny, E. H. Lee, and M. J. Bissell. 2007. 'Three-dimensional culture models of normal and malignant breast epithelial cells', Nat Methods, 4: 359-65.
Li, Ao, Yuchen Xu, Song Fan, Jialin Meng, Xufeng Shen, Qian Xiao, Yuan Li, Li Zhang, Xiansheng Zhang, Guanqing Wu, Chaozhao Liang, and Dianqing Wu. 2018. 'Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD', JCI insight, 3: e95874.
Li, X. 2011. 'Epigenetics and autosomal dominant polycystic kidney disease', Biochim Biophys Acta, 1812: 1213-8.
Liebau, Max Christoph, and Carsten Bergmann. 2016. 'Polycystic Kidney Disease: ADPKD and ARPKD.' in Denis F. Geary and Franz Schaefer (eds.), Pediatric Kidney Disease (Springer Berlin Heidelberg: Berlin, Heidelberg).
Liu, Y., A. Beyer, and R. Aebersold. 2016. 'On the Dependency of Cellular Protein Levels on mRNA Abundance', Cell, 165: 535-50.
Los, M., M. Mozoluk, D. Ferrari, A. Stepczynska, C. Stroh, A. Renz, Z. Herceg, Z. Q. Wang, and K. Schulze-Osthoff. 2002. 'Activation and caspase-mediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling', Mol Biol Cell, 13: 978-88.
Low, S. H., S. Vasanth, C. H. Larson, S. Mukherjee, N. Sharma, M. T. Kinter, M. E. Kane, T. Obara, and T. Weimbs. 2006. 'Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease', Dev Cell, 10: 57-69.
Majno, G., and I. Joris. 1995. 'Apoptosis, oncosis, and necrosis. An overview of cell death', Am J Pathol, 146: 3-15.
Mishra, J., C. Dent, R. Tarabishi, M. M. Mitsnefes, Q. Ma, C. Kelly, S. M. Ruff, K. Zahedi, M. Shao, J. Bean, K. Mori, J. Barasch, and P. Devarajan. 2005. 'Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery', Lancet, 365: 1231-8.
Mizushima, N., and M. Komatsu. 2011. 'Autophagy: renovation of cells and tissues', Cell, 147: 728-41.
Nauli, S. M., F. J. Alenghat, Y. Luo, E. Williams, P. Vassilev, X. Li, A. E. Elia, W. Lu, E. M. Brown, S. J. Quinn, D. E. Ingber, and J. Zhou. 2003. 'Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells', Nat Genet, 33: 129-37.
Nauli, S. M., S. Rossetti, R. J. Kolb, F. J. Alenghat, M. B. Consugar, P. C. Harris, D. E. Ingber, M. Loghman-Adham, and J. Zhou. 2006. 'Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction', J Am Soc Nephrol, 17: 1015-25.
Ong, A. C., and P. C. Harris. 2015. 'A polycystin-centric view of cyst formation and disease: the polycystins revisited', Kidney Int, 88: 699-710.
Parikh, C. R., N. K. Dahl, A. B. Chapman, J. E. Bost, C. L. Edelstein, D. M. Comer, R. Zeltner, X. Tian, J. J. Grantham, and S. Somlo. 2012. 'Evaluation of urine biomarkers of kidney injury in polycystic kidney disease', Kidney Int, 81: 784-90.
Pei, Y., A. D. Paterson, K. R. Wang, N. He, D. Hefferton, T. Watnick, G. G. Germino, P. Parfrey, S. Somlo, and P. St George-Hyslop. 2001. 'Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease', Am J Hum Genet, 68: 355-63.
Pei, Y., T. Watnick, N. He, K. Wang, Y. Liang, P. Parfrey, G. Germino, and P. St George-Hyslop. 1999. 'Somatic PKD2 mutations in individual kidney and liver cysts support a "two-hit" model of cystogenesis in type 2 autosomal dominant polycystic kidney disease', J Am Soc Nephrol, 10: 1524-9.
Pillai, S., D. D. Bikle, M. L. Mancianti, P. Cline, and M. Hincenbergs. 1990. 'Calcium regulation of growth and differentiation of normal human keratinocytes: modulation of differentiation competence by stages of growth and extracellular calcium', J Cell Physiol, 143: 294-302.
Pinto, M. C., A. H. Kihara, V. A. Goulart, F. M. Tonelli, K. N. Gomes, H. Ulrich, and R. R. Resende. 2015. 'Calcium signaling and cell proliferation', Cell Signal, 27: 2139-49.
Pinton, P., C. Giorgi, R. Siviero, E. Zecchini, and R. Rizzuto. 2008. 'Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis', Oncogene, 27: 6407-18.
Qian, F., T. J. Watnick, L. F. Onuchic, and G. G. Germino. 1996. 'The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I', Cell, 87: 979-87.
Reeders, S. T. 1992. 'Multilocus polycystic disease', Nat Genet, 1: 235-7.
Rossetti, S., V. J. Kubly, M. B. Consugar, K. Hopp, S. Roy, S. W. Horsley, D. Chauveau, L. Rees, T. M. Barratt, W. G. van't Hoff, P. Niaudet, V. E. Torres, and P. C. Harris. 2009. 'Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease', Kidney Int, 75: 848-55.
Rubinsztein, D. C., T. Shpilka, and Z. Elazar. 2012. 'Mechanisms of autophagosome biogenesis', Curr Biol, 22: R29-34.
Satlin, L. M., S. Sheng, C. B. Woda, and T. R. Kleyman. 2001. 'Epithelial Na(+) channels are regulated by flow', Am J Physiol Renal Physiol, 280: F1010-8.
Shen, S. J., Z. X. Hu, Q. H. Li, S. M. Wang, C. J. Song, D. D. Wu, J. L. He, J. C. Guan, and J. P. Shan. 2014. 'Implications of the changes in serum neutrophil gelatinase-associated lipocalin and cystatin C in patients with chronic kidney disease', Nephrology (Carlton), 19: 129-35.
Shillingford, J. M., K. B. Piontek, G. G. Germino, and T. Weimbs. 2010. 'Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1', J Am Soc Nephrol, 21: 489-97.
Shillingford, Jonathan M., Noel S. Murcia, Claire H. Larson, Seng Hui Low, Ryan Hedgepeth, Nicole Brown, Chris A. Flask, Andrew C. Novick, David A. Goldfarb, Albrecht Kramer-Zucker, Gerd Walz, Klaus B. Piontek, Gregory G. Germino, and Thomas Weimbs. 2006. 'The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease', Proceedings of the National Academy of Sciences, 103: 5466.
Starremans, P. G., X. Li, P. E. Finnerty, L. Guo, A. Takakura, E. G. Neilson, and J. Zhou. 2008. 'A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5' end of Pkd1', Kidney Int, 73: 1394-405.
Sweeney, W. E., Jr., and E. D. Avner. 2011. 'Diagnosis and management of childhood polycystic kidney disease', Pediatr Nephrol, 26: 675-92.
Talbot, J. J., J. M. Shillingford, S. Vasanth, N. Doerr, S. Mukherjee, M. T. Kinter, T. Watnick, and T. Weimbs. 2011. 'Polycystin-1 regulates STAT activity by a dual mechanism', Proc Natl Acad Sci U S A, 108: 7985-90.
Terryn, S., A. Ho, R. Beauwens, and O. Devuyst. 2011. 'Fluid transport and cystogenesis in autosomal dominant polycystic kidney disease', Biochim Biophys Acta, 1812: 1314-21.
Thivierge, C., A. Kurbegovic, M. Couillard, R. Guillaume, O. Cote, and M. Trudel. 2006. 'Overexpression of PKD1 causes polycystic kidney disease', Mol Cell Biol, 26: 1538-48.
Torres, V. E., A. B. Chapman, O. Devuyst, R. T. Gansevoort, J. J. Grantham, E. Higashihara, R. D. Perrone, H. B. Krasa, J. Ouyang, F. S. Czerwiec, and Tempo Trial Investigators. 2012. 'Tolvaptan in patients with autosomal dominant polycystic kidney disease', N Engl J Med, 367: 2407-18.
Torres, V. E., and P. C. Harris. 2009. 'Autosomal dominant polycystic kidney disease: the last 3 years', Kidney Int, 76: 149-68.
———. 2014. 'Strategies targeting cAMP signaling in the treatment of polycystic kidney disease', J Am Soc Nephrol, 25: 18-32.
Trudel, M., Q. Yao, and F. Qian. 2016. 'The Role of G-Protein-Coupled Receptor Proteolysis Site Cleavage of Polycystin-1 in Renal Physiology and Polycystic Kidney Disease', Cells, 5.
Tsai, Y. C., I. L. Teng, S. T. Jiang, Y. C. Lee, Y. Y. Chiou, and F. Y. Cheng. 2019. 'Safe Nanocomposite-Mediated Efficient Delivery of MicroRNA Plasmids for Autosomal Dominant Polycystic Kidney Disease (ADPKD) Therapy', Adv Healthc Mater, 8: e1801358.
Vareesangthip, K., K. Vareesangthip, C. Limwongse, and K. Reesukumal. 2017. 'Role of Urinary Neutrophil Gelatinase-Associated Lipocalin for Predicting the Severity of Renal Functions in Patients With Autosomal-Dominant Polycystic Kidney Disease', Transplant Proc, 49: 950-54.
Vermes, I., C. Haanen, H. Steffens-Nakken, and C. Reutelingsperger. 1995. 'A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V', J Immunol Methods, 184: 39-51.
Wallace, D. P. 2011. 'Cyclic AMP-mediated cyst expansion', Biochim Biophys Acta, 1812: 1291-300.
Wang, E., Y. Y. Chiou, W. Y. Jeng, H. K. Lin, H. H. Lin, H. J. Chin, C. K. Leo Wang, S. S. Yu, S. C. Tsai, C. Y. Chiang, P. H. Cheng, H. J. Lin, S. T. Jiang, S. T. Chiu, and H. M. Hsieh-Li. 2017. 'Overexpression of exogenous kidney-specific Ngal attenuates progressive cyst development and prolongs lifespan in a murine model of polycystic kidney disease', Kidney Int, 91: 412-22.
Watkins, P. B., J. H. Lewis, N. Kaplowitz, D. H. Alpers, J. D. Blais, D. M. Smotzer, H. Krasa, J. Ouyang, V. E. Torres, F. S. Czerwiec, and C. A. Zimmer. 2015. 'Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database', Drug Saf, 38: 1103-13.
Watnick, T., N. He, K. Wang, Y. Liang, P. Parfrey, D. Hefferton, P. St George-Hyslop, G. Germino, and Y. Pei. 2000. 'Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations', Nat Genet, 25: 143-4.
Wei, F., A. Karihaloo, Z. Yu, A. Marlier, P. Seth, S. Shibazaki, T. Wang, V. P. Sukhatme, S. Somlo, and L. G. Cantley. 2008. 'Neutrophil gelatinase-associated lipocalin suppresses cyst growth by Pkd1 null cells in vitro and in vivo', Kidney Int, 74: 1310-18.
Weimbs, T. 2011. 'Third-hit signaling in renal cyst formation', J Am Soc Nephrol, 22: 793-5.
Wu, G., X. Tian, S. Nishimura, G. S. Markowitz, V. D'Agati, J. H. Park, L. Yao, L. Li, L. Geng, H. Zhao, W. Edelmann, and S. Somlo. 2002. 'Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease', Hum Mol Genet, 11: 1845-54.
Yamaguchi, T., S. Nagao, D. P. Wallace, F. A. Belibi, B. D. Cowley, J. C. Pelling, and J. J. Grantham. 2003. 'Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys', Kidney Int, 63: 1983-94.
Yamaguchi, T., J. C. Pelling, N. T. Ramaswamy, J. W. Eppler, D. P. Wallace, S. Nagao, L. A. Rome, L. P. Sullivan, and J. J. Grantham. 2000. 'cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway', Kidney Int, 57: 1460-71.
Yamamoto, K. K., G. A. Gonzalez, W. H. Biggs, 3rd, and M. R. Montminy. 1988. 'Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB', Nature, 334: 494-8.
Zhu, P., C. J. Sieben, X. Xu, P. C. Harris, and X. Lin. 2017. 'Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model', Hum Mol Genet, 26: 158-72.