Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment
Abstract
1. Introduction
2. Polycystic Kidney Disease
3. Mammalian Target of Rapamycin (mTOR) Activation in PKD
4. Glucose Metabolism, Glycolysis, Oxidative Phosphorylation, and the Warburg Effect
5. Amino Acid Metabolism
6. ERK-AMPK
7. Fatty Acid Oxidation
8. Sirtuin
9. Cilia, mTOR, and Cellular Metabolism
10. Emerging Treatment Options
11. Conclusions
Funding
Conflicts of Interest
Abbreviations
Acetyl-CoA | acetyl coenzyme A |
ADP | adenosine diphosphate |
ADPKD | autosomal dominant polycystic kidney disease |
α-KG | alpha-ketoglutarate |
AMPK | adenosine monophospahte-activated protein kinase |
ARPKD | autosomal recessive polycystic kidney disease |
ASNS | asparagine synthethase |
ASS1 | arginosuccinate synthase 1 |
ATP | adenosine triphosphate |
cAMP | cyclic adenosine monophosphate |
BHB | β-hydroxybutyrate |
CKD | chronic kidney disease |
eGFR | estimated glomerular filtration rate |
ERK | extracellular-signal regulated kinase |
FADH | flavin adenine dinucleotide |
HIF 1 | Hypoxia-inducible factor 1 |
HNF4α | Hepatocyte nuclear factor 4 alpha |
LKB1 | Liver kinase B1 |
MAPK | mitogen-activated protein kinase pathway |
MEFs | mouse embryonic fibroblasts |
MRI | magnetic resonance imaging |
mTOR | mammalian target of rapamycine |
mTORC1 | mammalian target of rapamycine complex 1 |
mTORC2 | mammalian target of rapamycine complex 2 |
NADH | nicotinamide adenine dinucleotide |
OAA | oxalacetate |
PCC | polycystin complex |
PC1 | Polycystin 1 |
PC2 | Polycystin 2 |
PKD | polycystic kidney disease |
PPAR- α | Peroxisome proliferator-activated receptor alpha |
SIRT-1 | Sirtuin-1 |
SREBP-1 | sterol regulatory element-binding protein 1 |
TCA | tricarboxylic acid cycle |
TRPs | transient receptor potential ion channels |
TSC | transient receptor potential ion channels |
References
- Gabow, P.A. Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 1993, 329, 332–342. [Google Scholar] [CrossRef]
- Torres, V.E.; Harris, P.C. Polycystic kidney disease: Genes, proteins, animal models, disease mechanisms and therapeutic opportunities. J. Intern. Med. 2007, 261, 17–31. [Google Scholar] [CrossRef]
- Cramer, M.T.; Guay-Woodford, L.M. Cystic Kidney Disease: A Primer. Adv. Chronic Kidney Dis. 2015, 22, 297–305. [Google Scholar] [CrossRef] [PubMed]
- De Rechter, S.; Breysem, L.; Mekahli, D. Is Autosomal Dominant Polycystic Kidney Disease Becoming a Pediatric Disorder? Front. Pediatr. 2017, 5. [Google Scholar] [CrossRef] [PubMed]
- Cordido, A.; Besada-Cerecedo, L.; García-González, M.A. The Genetic and Cellular Basis of Autosomal Dominant Polycystic Kidney Disease—A Primer for Clinicians. Front. Pediatr. 2017, 5. [Google Scholar] [CrossRef]
- Bergmann, C. Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses. Front. Pediatr. 2018, 5. [Google Scholar] [CrossRef] [PubMed]
- Bergmann, C.; Guay-Woodford, L.M.; Harris, P.C.; Horie, S.; Peters, D.J.M.; Torres, V.E. Polycystic kidney disease. Nat. Rev. Dis. Prim. 2018, 4, 50. [Google Scholar] [CrossRef]
- Chebib, F.T.; Torres, V.E. Recent Advances in the Management of Autosomal Dominant Polycystic Kidney Disease. Clin. J. Am. Soc. Nephrol. 2018, 13, 1765–1776. [Google Scholar] [CrossRef]
- Torres, V.E.; Chapman, A.B.; Devuyst, O.; Gansevoort, R.T.; Grantham, J.J.; Higashihara, E.; Perrone, R.D.; Krasa, H.B.; Ouyang, J.; Czerwiec, F.S.; et al. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2012, 367, 2407–2418. [Google Scholar] [CrossRef]
- Torres, V.E.; Chapman, A.B.; Devuyst, O.; Gansevoort, R.T.; Perrone, R.D.; Koch, G.; Ouyang, J.; McQuade, R.D.; Blais, J.D.; Czerwiec, F.S.; et al. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2017, 377, 1930–1942. [Google Scholar] [CrossRef]
- Rinschen, M.M.; Schermer, B.; Benzing, T. Vasopressin-2 Receptor Signaling and Autosomal Dominant Polycystic Kidney Disease: From Bench to Bedside and Back Again. J. Am. Soc. Nephrol. 2014, 25, 1140–1147. [Google Scholar] [CrossRef] [PubMed]
- Chakraborty, S.; McHugh, K. Cystic diseases of the kidney in children. Imaging 2005, 17, 69–75. [Google Scholar] [CrossRef]
- Hoyer, P.F. Clinical manifestations of autosomal recessive polycystic kidney disease. Curr. Opin. Pediatr. 2015, 27, 186–192. [Google Scholar] [CrossRef] [PubMed]
- Ganschow, R.; Hoppe, B. Review of combined liver and kidney transplantation in children. Pediatr. Transplant. 2015, 19, 820–826. [Google Scholar] [CrossRef] [PubMed]
- Ebner, K.; Feldkoetter, M.; Ariceta, G.; Bergmann, C.; Buettner, R.; Doyon, A.; Duzova, A.; Göbel, H.; Haffner, D.; Hero, B.; et al. Rationale, design and objectives of ARegPKD, a European ARPKD registry study. BMC Nephrol. 2015, 16, 22. [Google Scholar] [CrossRef] [PubMed]
- Ebner, K.; Schaefer, F.; Liebau, M.C.; The ARegPKD Consortium; Eid, L.A.; Ranguelov, N.; Adams, B.; Van Hoeck, K.; Raes, A.; Mekahli, D.; et al. Recent Progress of the ARegPKD Registry Study on Autosomal Recessive Polycystic Kidney Disease. Front. Pediatr. 2017, 5. [Google Scholar] [CrossRef]
- Alzarka, B.; Morizono, H.; Bollman, J.W.; Kim, D.; Guay-Woodford, L.M. Design and Implementation of the Hepatorenal Fibrocystic Disease Core Center Clinical Database: A Centralized Resource for Characterizing Autosomal Recessive Polycystic Kidney Disease and Other Hepatorenal Fibrocystic Diseases. Front. Pediatr. 2017, 5. [Google Scholar] [CrossRef]
- Lu, H.; Galeano, M.C.R.; Ott, E.; Kaeslin, G.; Kausalya, P.J.; Kramer, C.; Ortiz-Brüchle, N.; Hilger, N.; Metzis, V.; Hiersche, M.; et al. Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nat. Genet. 2017, 49, 1025–1034. [Google Scholar] [CrossRef]
- Follit, J.A.; Li, L.; Vucica, Y.; Pazour, G.J. The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. J. Cell Boil. 2010, 188, 21–28. [Google Scholar] [CrossRef]
- Kaimori, J.-Y.; Nagasawa, Y.; Menezes, L.F.; Garcia-Gonzalez, M.A.; Deng, J.; Imai, E.; Onuchic, L.F.; Guay-Woodford, L.M.; Germino, G.G. Polyductin undergoes notch-like processing and regulated release from primary cilia. Hum. Mol. Genet. 2007, 16, 942–956. [Google Scholar] [CrossRef]
- Hiesberger, T.; Gourley, E.; Erickson, A.; Koulen, P.; Ward, C.J.; Masyuk, T.V.; LaRusso, N.F.; Harris, P.C.; Igarashi, P. Proteolytic Cleavage and Nuclear Translocation of Fibrocystin Is Regulated by Intracellular Ca2+ and Activation of Protein Kinase C. J. Boil. Chem. 2006, 281, 34357–34364. [Google Scholar] [CrossRef] [PubMed]
- Kaimori, J.-Y.; Lin, C.-C.; Outeda, P.; Garcia-Gonzalez, M.A.; Menezes, L.F.; Hartung, E.A.; Li, A.; Wu, G.; Fujita, H.; Sato, Y.; et al. NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology. Sci. Rep. 2017, 7, 1–16. [Google Scholar] [CrossRef] [PubMed]
- Outeda, P.; Menezes, L.; Hartung, E.A.; Bridges, S.; Zhou, F.; Zhu, X.; Xu, H.; Huang, Q.; Yao, Q.; Qian, F.; et al. A novel model of autosomal recessive polycystic kidney questions the role of the fibrocystin C-terminus in disease mechanism. Kidney Int. 2017, 92, 1130–1144. [Google Scholar] [CrossRef] [PubMed]
- Garcia-Gonzalez, M.A.; Menezes, L.F.; Piontek, K.B.; Kaimori, J.; Huso, D.L.; Watnick, T.; Onuchic, L.F.; Guay-Woodford, L.M.; Germino, G.G. Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway. Hum. Mol. Genet. 2007, 16, 1940–1950. [Google Scholar] [CrossRef]
- Moser, M.; Matthiesen, S.; Kirfel, J.; Schorle, H.; Bergmann, C.; Senderek, J.; Zerres, K.; Buettner, R.; Rudnik-Schöneborn, S. A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD). Hepatology 2005, 41, 1113–1121. [Google Scholar] [CrossRef]
- Woollard, J.; Punyashtiti, R.; Richardson, S.; Masyuk, T.; Whelan, S.; Huang, B.; Lager, D.; Vandeursen, J.; Torres, V.; Gattone, V.; et al. A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation. Kidney Int. 2007, 72, 328–336. [Google Scholar] [CrossRef]
- Chebib, F.T.; Torres, V.E. Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016. Am. J. Kidney Dis. 2015, 67, 792–810. [Google Scholar] [CrossRef]
- Krishnappa, V.; Vinod, P.; Deverakonda, D.; Raina, R. Autosomal dominant polycystic kidney disease and the heart and brain. Clevel. Clin. J. Med. 2017, 84, 471–481. [Google Scholar] [CrossRef]
- Bergmann, C.; Von Bothmer, J.; Brüchle, N.O.; Venghaus, A.; Frank, V.; Fehrenbach, H.; Hampel, T.; Pape, L.; Buske, A.; Jonsson, J.; et al. Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. J. Am. Soc. Nephrol. 2011, 22, 2047–2056. [Google Scholar] [CrossRef]
- Harris, P.C.; Rossetti, S. Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat. Rev. Nephrol. 2010, 6, 197–206. [Google Scholar] [CrossRef]
- Harris, P.C.; Hopp, K. The Mutation, a Key Determinant of Phenotype in ADPKD. J. Am. Soc. Nephrol. 2013, 24, 868–870. [Google Scholar] [CrossRef] [PubMed]
- Gall, E.C.-L.; Audrézet, M.-P.; Chen, J.-M.; Hourmant, M.; Morin, M.-P.; Perrichot, R.; Charasse, C.; Whebe, B.; Renaudineau, E.; Jousset, P.; et al. Type of PKD1 Mutation Influences Renal Outcome in ADPKD. J. Am. Soc. Nephrol. 2013, 24, 1006–1013. [Google Scholar] [CrossRef] [PubMed]
- Porath, B.; Gainullin, V.G.; Gall, E.C.-L.; Dillinger, E.K.; Heyer, C.M.; Hopp, K.; Edwards, M.E.; Madsen, C.D.; Mauritz, S.R.; Banks, C.J.; et al. Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. Am. J. Hum. Genet. 2016, 98, 1193–1207. [Google Scholar] [CrossRef] [PubMed]
- Gall, E.C.-L.; Torres, V.E.; Harris, P.C. Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases. J. Am. Soc. Nephrol. 2017, 29, 13–23. [Google Scholar] [CrossRef] [PubMed]
- Irazabal, M.V.; Rangel, L.J.; Bergstralh, E.J.; Osborn, S.L.; Harmon, A.J.; Sundsbak, J.L.; Bae, K.T.; Chapman, A.B.; Grantham, J.J.; Mrug, M.; et al. Imaging Classification of Autosomal Dominant Polycystic Kidney Disease: A Simple Model for Selecting Patients for Clinical Trials. J. Am. Soc. Nephrol. 2014, 26, 160–172. [Google Scholar] [CrossRef]
- Gall, E.C.-L.; Audrézet, M.-P.; Rousseau, A.; Hourmant, M.; Renaudineau, E.; Charasse, C.; Morin, M.-P.; Moal, M.-C.; Dantal, J.; Wehbe, B.; et al. The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2015, 27, 942–951. [Google Scholar] [CrossRef]
- Chang, M.-Y.; Ong, A. Targeting new cellular disease pathways in autosomal dominant polycystic kidney disease. Nephrol. Dial. Transplant. 2017, 33, 1310–1316. [Google Scholar] [CrossRef]
- Leonhard, W.N.; Happe, H.; Peters, D.J. Variable Cyst Development in Autosomal Dominant Polycystic Kidney Disease: The Biologic Context. J. Am. Soc. Nephrol. 2016, 27, 3530–3538. [Google Scholar] [CrossRef]
- Ong, A.; Harris, P.C. A polycystin-centric view of cyst formation and disease: The polycystins revisited. Kidney Int. 2015, 88, 699–710. [Google Scholar] [CrossRef]
- Olson, R.J.; Hopp, K.; Wells, H.; Smith, J.M.; Furtado, J.; Constans, M.M.; Escobar, D.L.; Geurts, A.M.; Torres, V.E.; Harris, P.C. Synergistic Genetic Interactions between Pkhd1 and Pkd1 Result in an ARPKD-Like Phenotype in Murine Models. J. Am. Soc. Nephrol. 2019, 30, 2113–2127. [Google Scholar] [CrossRef]
- Kim, I.; Li, C.; Liang, D.; Chen, X.-Z.; Coffy, R.J.; Ma, J.; Zhao, P.; Wu, G. Polycystin-2 Expression Is Regulated by a PC2-binding Domain in the Intracellular Portion of Fibrocystin. J. Boil. Chem. 2008, 283, 31559–31566. [Google Scholar] [CrossRef] [PubMed]
- Lea, W.A.; McGreal, K.; Sharma, M.; Parnell, S.C.; Zelenchuk, L.; Charlesworth, M.C.; Madden, B.J.; Johnson, K.L.; McCormick, D.J.; Hogan, M.C.; et al. Analysis of the polycystin complex (PCC) in human urinary exosome–like vesicles (ELVs). Sci. Rep. 2020, 10, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Qian, F.; Watnick, T.J.; Onuchic, L.F.; Germino, G.G. The Molecular Basis of Focal Cyst Formation in Human Autosomal Dominant Polycystic Kidney Disease Type I. Cell 1996, 87, 979–987. [Google Scholar] [CrossRef]
- Watnick, T.; E Torres, V.; A Gandolph, M.; Qian, F.; Onuchic, L.F.; Klinger, K.W.; Landes, G.; Germino, G.G. Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease. Mol. Cell 1998, 2, 247–251. [Google Scholar] [CrossRef]
- Pei, Y.; Watnick, T.; He, N.; Wang, K.; Liang, Y.; Parfrey, P.; Germino, G.; George-Hyslop, P.S. 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. 1999, 10, 1524–1529. [Google Scholar]
- Weimbs, T. Third-hit signaling in renal cyst formation. J. Am. Soc. Nephrol. 2011, 22, 793–795. [Google Scholar] [CrossRef]
- Yamaguchi, T.; Nagao, S.; Wallace, D.P.; Belibi, F.A.; Cowley, B.D.; Pelling, J.C.; Grantham, J.J.; Grantham, J.J. Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int. 2003, 63, 1983–1994. [Google Scholar] [CrossRef]
- Zhou, J.X.; Fan, L.X.; Li, X.; Calvet, J.P.; Li, X. TNFα Signaling Regulates Cystic Epithelial Cell Proliferation through Akt/mTOR and ERK/MAPK/Cdk2 Mediated Id2 Signaling. PLOS ONE 2015, 10, e0131043. [Google Scholar] [CrossRef]
- Seeger-Nukpezah, T.; Geynisman, D.M.; Nikonova, A.S.; Benzing, T.; Golemis, E.A. The hallmarks of cancer: Relevance to the pathogenesis of polycystic kidney disease. Nat. Rev. Nephrol. 2015, 11, 515–534. [Google Scholar] [CrossRef]
- Wahl, P.R.; Serra, A.L.; Le Hir, M.; Molle, K.D.; Hall, M.N.; Wüthrich, R.P. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol. Dial. Transplant. 2005, 21, 598–604. [Google Scholar] [CrossRef]
- Shillingford, J.M.; Murcia, N.S.; Larson, C.H.; Low, S.H.; Hedgepeth, R.; Brown, N.; Flask, C.A.; Novick, A.C.; Goldfarb, D.A.; Kramer-Zucker, A.; et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl. Acad. Sci. USA 2006, 103, 5466–5471. [Google Scholar] [CrossRef] [PubMed]
- Lieberthal, W.; Levine, J.S. Mammalian target of rapamycin and the kidney. I. The signaling pathway. Am. J. Physiol. Physiol. 2012, 303, F1–F10. [Google Scholar] [CrossRef] [PubMed]
- Mannaa, M.; Krämer, S.; Boschmann, M.; Gollasch, M. mTOR and regulation of energy homeostasis in humans. J. Mol. Med. 2013, 91, 1167–1175. [Google Scholar] [CrossRef] [PubMed]
- Lieberthal, W.; Levine, J.S. The Role of the Mammalian Target Of Rapamycin (mTOR) in Renal Disease. J. Am. Soc. Nephrol. 2009, 20, 2493–2502. [Google Scholar] [CrossRef] [PubMed]
- Rabanal-Ruiz, Y.; Korolchuk, V.I. mTORC1 and Nutrient Homeostasis: The Central Role of the Lysosome. Int. J. Mol. Sci. 2018, 19, 818. [Google Scholar] [CrossRef]
- Huber, T.B.; Walz, G.; Kuehn, E.W. mTOR and rapamycin in the kidney: Signaling and therapeutic implications beyond immunosuppression. Kidney Int. 2011, 79, 502–511. [Google Scholar] [CrossRef] [PubMed]
- Schmeisser, K.; Parker, J.A. Pleiotropic Effects of mTOR and Autophagy During Development and Aging. Front. Cell Dev. Boil. 2019, 7. [Google Scholar] [CrossRef]
- Walz, G.; Budde, K.; Mannaa, M.; Nurnberger, J.; Wanner, C.; Sommerer, C.; Kunzendorf, U.; Banas, B.; Hörl, W.H.; Obermüller, N.; et al. Everolimus in Patients with Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2010, 363, 830–840. [Google Scholar] [CrossRef]
- Grantham, J.J.; Torres, V.E.; Chapman, A.B.; Guay-Woodford, L.M.; Bae, K.T.; King, B.F.; Wetzel, L.H.; Baumgarten, D.A.; Kenney, P.J.; Harris, P.C.; et al. Volume Progression in Polycystic Kidney Disease. N. Engl. J. Med. 2006, 354, 2122–2130. [Google Scholar] [CrossRef]
- Bae, K.T.; Tao, C.; Wang, J.; Kaya, D.; Wu, Z.; Bae, J.T.; Chapman, A.B.; Torres, V.E.; Grantham, J.J.; Mrug, M.; et al. Novel approach to estimate kidney and cyst volumes using mid-slice magnetic resonance images in polycystic kidney disease. Am. J. Nephrol. 2013, 38, 333–341. [Google Scholar] [CrossRef]
- Bhutani, H.; Smith, V.; Rahbari-Oskoui, F.; Mittal, A.; Grantham, J.J.; Torres, V.E.; Mrug, M.; Bae, K.T.; Wu, Z.; Ge, Y.; et al. A comparison of ultrasound and magnetic resonance imaging shows that kidney length predicts chronic kidney disease in autosomal dominant polycystic kidney disease. Kidney Int. 2015, 88, 146–151. [Google Scholar] [CrossRef] [PubMed]
- Tangri, N.; Hougen, I.; Alam, A.; Perrone, R.; McFarlane, P.; Pei, Y. Total Kidney Volume as a Biomarker of Disease Progression in Autosomal Dominant Polycystic Kidney Disease. Can. J. Kidney Heal. Dis. 2017, 4. [Google Scholar] [CrossRef] [PubMed]
- Serra, A.L.; Kistler, A.D.; Poster, D.; Struker, M.; Wüthrich, R.P.; Weishaupt, D.; Tschirch, F. Clinical proof-of-concept trial to assess the therapeutic effect of sirolimus in patients with autosomal dominant polycystic kidney disease: SUISSE ADPKD study. BMC Nephrol. 2007, 8, 13. [Google Scholar] [CrossRef] [PubMed]
- Serra, A.L.; Poster, D.; Kistler, A.D.; Krauer, F.; Raina, S.; Young, J.; Rentsch, K.M.; Spanaus, K.S.; Senn, O.; Kristanto, P.; et al. Sirolimus and Kidney Growth in Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2010, 363, 820–829. [Google Scholar] [CrossRef]
- Zafar, I.; Ravichandran, K.; Belibi, F.A.; Doctor, R.B.; Edelstein, C.L. Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease. Kidney Int. 2010, 78, 754–761. [Google Scholar] [CrossRef]
- Tao, Y.; Kim, J.; Schrier, R.W.; Edelstein, C.L. Rapamycin Markedly Slows Disease Progression in a Rat Model of Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2004, 16, 46–51. [Google Scholar] [CrossRef]
- Nagao, S.; Kugita, M.; Yoshihara, D.; Yamaguchi, T. Animal models for human polycystic kidney disease. Exp. Anim. 2012, 61, 477–488. [Google Scholar] [CrossRef]
- Novalic, Z.; Van Der Wal, A.M.; Leonhard, W.N.; Koehl, G.; Breuning, M.H.; Geissler, E.K.; De Heer, E.; Peters, D.J. Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2012, 23, 842–853. [Google Scholar] [CrossRef]
- Canaud, G.; Knebelmann, B.; Harris, P.C.; Vrtovsnik, F.; Correas, J.; Pallet, N.; Heyer, C.M.; Letavernier, E.; Bienaimé, F.; Thervet, E.; et al. Therapeutic mTOR Inhibition in Autosomal Dominant Polycystic Kidney Disease: What Is the Appropriate Serum Level? Arab. Archaeol. Epigr. 2010, 10, 1701–1706. [Google Scholar] [CrossRef]
- Jardine, M.; Liyanage, T.; Buxton, E.; Perkovic, V. mTOR inhibition in autosomal-dominant polycystic kidney disease (ADPKD): The question remains open. Nephrol. Dial. Transplant. 2012, 28, 242–244. [Google Scholar] [CrossRef]
- Shillingford, J.M.; Leamon, C.P.; Vlahov, I.R.; Weimbs, T. Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2012, 23, 1674–1681. [Google Scholar] [CrossRef] [PubMed]
- Grahammer, F.; Wanner, N.; Huber, T.B. mTOR controls kidney epithelia in health and disease. Nephrol. Dial. Transplant. 2014, 29, i9–i18. [Google Scholar] [CrossRef] [PubMed]
- Distefano, G.; Boca, M.; Rowe, I.; Wodarczyk, C.; Ma, L.; Piontek, K.B.; Germino, G.G.; Pandolfi, P.P.; Boletta, A. Polycystin-1 Regulates Extracellular Signal-Regulated Kinase-Dependent Phosphorylation of Tuberin To Control Cell Size through mTOR and Its Downstream Effectors S6K and 4EBP1. Mol. Cell. Boil. 2009, 29, 2359–2371. [Google Scholar] [CrossRef] [PubMed]
- Pema, M.; Drusian, L.; Chiaravalli, M.; Castelli, M.; Yao, Q.; Ricciardi, S.; Somlo, S.; Qian, F.; Biffo, S.; Boletta, A. mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. Nat. Commun. 2016, 7, 10786. [Google Scholar] [CrossRef] [PubMed]
- Wang, S.; Wu, M.; Yao, G.; Zhang, J.; Zhou, J. The Cytoplasmic Tail of FPC Antagonizes the Full-Length Protein in the Regulation of mTOR Pathway. PLoS ONE 2014, 9, e95630. [Google Scholar] [CrossRef] [PubMed]
- Fischer, D.-C.; Jacoby, U.; Pape, L.; Ward, C.; Kuwertz-Broeking, E.; Renken, C.; Nizze, H.; Querfeld, U.; Rudolph, B.; Mueller-Wiefel, D.E.; et al. Activation of the AKT/mTOR pathway in autosomal recessive polycystic kidney disease (ARPKD). Nephrol. Dial. Transplant. 2009, 24, 1819–1827. [Google Scholar] [CrossRef] [PubMed]
- Ren, X.S.; Sato, Y.; Harada, K.; Sasaki, M.; Furubo, S.; Song, J.Y.; Nakanuma, Y. Activation of the PI3K/mTOR Pathway Is Involved in Cystic Proliferation of Cholangiocytes of the PCK Rat. PLoS ONE 2014, 9, e87660. [Google Scholar] [CrossRef]
- Zhu, P.; Sieben, C.J.; Xu, X.; Harris, P.C.; Lin, X. Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model. Hum. Mol. Genet. 2016, 26, 158–172. [Google Scholar] [CrossRef]
- Rowe, I.; Boletta, A. Defective metabolism in polycystic kidney disease: Potential for therapy and open questions. Nephrol. Dial. Transplant. 2014, 29, 1480–1486. [Google Scholar] [CrossRef][Green Version]
- Corbet, C.; Feron, O. Cancer cell metabolism and mitochondria: Nutrient plasticity for TCA cycle fueling. Biochim. et Biophys. Acta (BBA)-Rev. Cancer 2017, 1868, 7–15. [Google Scholar] [CrossRef]
- Warburg, O. On the Origin of Cancer Cells. Science 1956, 123, 309–314. [Google Scholar] [CrossRef] [PubMed]
- Burns, J.S.; Manda, G. Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance. Int. J. Mol. Sci. 2017, 18, 2755. [Google Scholar] [CrossRef]
- Potter, M.; Newport, E.; Morten, K.J. The Warburg effect: 80 years on. Biochem. Soc. Trans. 2016, 44, 1499–1505. [Google Scholar] [CrossRef] [PubMed]
- Heiden, M.G.V.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 2009, 324, 1029–1033. [Google Scholar] [CrossRef] [PubMed]
- Pelicano, H.; Martin, D.S.; Xu, R.-H.; Huang, P. Glycolysis inhibition for anticancer treatment. Oncogene 2006, 25, 4633–4646. [Google Scholar] [CrossRef] [PubMed]
- Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The Next Generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed]
- Scalise, M.; Pochini, L.; Galluccio, M.; Console, L.; Indiveri, C. Glutamine Transport and Mitochondrial Metabolism in Cancer Cell Growth. Front. Oncol. 2017, 7. [Google Scholar] [CrossRef]
- Yu, L.; Chen, X.; Sun, X.; Wang, L.; Chen, S. The Glycolytic Switch in Tumors: How Many Players Are Involved? J. Cancer 2017, 8, 3430–3440. [Google Scholar] [CrossRef]
- Rowe, I.; Chiaravalli, M.; Mannella, V.; Ulisse, V.; Quilici, G.; Pema, M.; Song, X.W.; Xu, H.; Mari, S.; Qian, F.; et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat. Med. 2013, 19, 488–493. [Google Scholar] [CrossRef]
- Song, X.; Di Giovanni, V.; He, N.; Wang, K.; Ingram, A.; Rosenblum, N.D.; Pei, Y. Systems biology of autosomal dominant polycystic kidney disease (ADPKD): Computational identification of gene expression pathways and integrated regulatory networks. Hum. Mol. Genet. 2009, 18, 2328–2343. [Google Scholar] [CrossRef]
- Chiaravalli, M.; Rowe, I.; Mannella, V.; Quilici, G.; Canu, T.; Bianchi, V.; Gurgone, A.; Antunes, S.; D’Adamo, P.; Esposito, A.; et al. 2-Deoxy-d-Glucose Ameliorates PKD Progression. J. Am. Soc. Nephrol. 2015, 27, 1958–1969. [Google Scholar] [CrossRef] [PubMed]
- Riwanto, M.; Kapoor, S.; Rodriguez, D.; Edenhofer, I.; Segerer, S.; Wüthrich, R.P. Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease. PLoS ONE 2016, 11, e0146654. [Google Scholar] [CrossRef] [PubMed]
- Lian, X.; Zhao, J.; Wu, X.; Zhang, Y.; Li, Q.; Lin, S.; Bai, X.-Y.; Chen, X. The changes in glucose metabolism and cell proliferation in the kidneys of polycystic kidney disease mini-pig models. Biochem. Biophys. Res. Commun. 2017, 488, 374–381. [Google Scholar] [CrossRef] [PubMed]
- Lin, C.-C.; Kurashige, M.; Liu, Y.; Terabayashi, T.; Ishimoto, Y.; Wang, T.; Choudhary, V.; Hobbs, R.; Liu, L.-K.; Lee, P.-H.; et al. A cleavage product of Polycystin-1 is a mitochondrial matrix protein that affects mitochondria morphology and function when heterologously expressed. Sci. Rep. 2018, 8, 2743. [Google Scholar] [CrossRef]
- Ishimoto, Y.; Inagi, R.; Yoshihara, D.; Kugita, M.; Nagao, S.; Shimizu, A.; Takeda, N.; Wake, M.; Honda, K.; Zhou, J.; et al. Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease. Mol. Cell. Boil. 2017, 37, e00337-17. [Google Scholar] [CrossRef]
- Podrini, C.; Cassina, L.; Boletta, A. Metabolic reprogramming and the role of mitochondria in polycystic kidney disease. Cell. Signal. 2020, 67. [Google Scholar] [CrossRef]
- Padovano, V.; Kuo, I.Y.; Stavola, L.K.; Aerni, H.R.; Flaherty, B.J.; Chapin, H.C.; Ma, M.; Somlo, S.; Boletta, A.; Ehrlich, B.E.; et al. The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function. Mol. Boil. Cell 2017, 28, 261–269. [Google Scholar] [CrossRef]
- Kuo, I.Y.; Brill, A.L.; Lemos, F.O.; Jiang, J.Y.; Falcone, J.L.; Kimmerling, E.P.; Cai, Y.; Dong, K.; Kaplan, D.L.; Wallace, D.P.; et al. Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2. Sci. Signal. 2019, 12, eaat7397. [Google Scholar] [CrossRef]
- Cassina, L.; Chiaravalli, M.; Boletta, A. Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression. FASEB J. 2020, 34, 6493–6507. [Google Scholar] [CrossRef]
- DeBerardinis, R.J.; Mancuso, A.; Daikhin, E.; Nissim, I.; Yudkoff, M.; Wehrli, S.; Thompson, C.B. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl. Acad. Sci. USA 2007, 104, 19345–19350. [Google Scholar] [CrossRef]
- Hwang, V.J.; Kim, J.; Rand, A.; Yang, C.; Sturdivant, S.; Hammock, B.; Bell, P.D.; Guay-Woodford, L.M.; Weiss, R.H. The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate. Am. J. Physiol. Physiol. 2015, 309, F492–F498. [Google Scholar] [CrossRef] [PubMed]
- Flowers, E.M.; Sudderth, J.; Zacharias, L.; Mernaugh, G.; Zent, R.; DeBerardinis, R.J.; Carroll, T.J. Lkb1 deficiency confers glutamine dependency in polycystic kidney disease. Nat. Commun. 2018, 9, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Podrini, C.; Rowe, I.; Pagliarini, R.; Costa, A.S.H.; Chiaravalli, M.; Di Meo, I.; Kim, H.; Distefano, G.; Tiranti, V.; Qian, F.; et al. Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways. Commun. Boil. 2018, 1, 194. [Google Scholar] [CrossRef] [PubMed]
- Trott, J.F.; Hwang, V.J.; Ishimaru, T.; Chmiel, K.J.; Zhou, J.X.; Shim, K.; Stewart, B.J.; Mahjoub, M.; Jen, K.-Y.; Barupal, D.K.; et al. Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis. Am. J. Physiol. Physiol. 2018, 315, F1855–F1868. [Google Scholar] [CrossRef] [PubMed]
- Hardie, D.; Carling, D.; Carlson, M. THE AMP-ACTIVATED/SNF1 PROTEIN KINASE SUBFAMILY: Metabolic Sensors of the Eukaryotic Cell? Annu. Rev. Biochem. 1998, 67, 821–855. [Google Scholar] [CrossRef] [PubMed]
- Herzig, S.; Shaw, R.J. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Boil. 2017, 19, 121–135. [Google Scholar] [CrossRef]
- Olivier, S.; Foretz, M.; Viollet, B. Promise and challenges for direct small molecule AMPK activators. Biochem. Pharmacol. 2018, 153, 147–158. [Google Scholar] [CrossRef]
- Jeon, S.-M. Regulation and function of AMPK in physiology and diseases. Exp. Mol. Med. 2016, 48, e245. [Google Scholar] [CrossRef]
- Safe, S.; Nair, V.; Karki, K.; Naira, V. Metformin-induced anticancer activities: Recent insights. Boil. Chem. 2018, 399, 321–335. [Google Scholar] [CrossRef]
- Ikhlas, S.; Ahmad, M. Metformin: Insights into its anticancer potential with special reference to AMPK dependent and independent pathways. Life Sci. 2017, 185, 53–62. [Google Scholar] [CrossRef]
- Wheaton, W.W.; Weinberg, S.E.; Hamanaka, R.B.; Soberanes, S.; Sullivan, L.B.; Anso, E.; Glasauer, A.; Dufour, E.; Mutlu, G.M.; Budigner, G.S.; et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 2014, 3, 18. [Google Scholar] [CrossRef] [PubMed]
- Piel, S.; Ehinger, K.H.J.; Elmér, E.; Hansson, M. Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition. Acta Physiol. 2014, 213, 171–180. [Google Scholar] [CrossRef] [PubMed]
- Takiar, V.; Nishio, S.; Seo-Mayer, P.; King, J.D.; Li, H.; Zhang, L.; Karihaloo, A.; Hallows, K.R.; Somlo, S.; Caplan, M.J. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl. Acad. Sci. USA 2011, 108, 2462–2467. [Google Scholar] [CrossRef] [PubMed]
- Mekhali, D.; Decuypere, J.-P.; Sammels, E.; Welkenhuyzen, K.; Schoeber, J.; Audrézet, M.-P.; Corvelyn, A.; Dechênes, G.; Ong, A.C.M.; Wilmer, M.J.; et al. Polycystin-1 but not polycystin-2 deficiency causes upregulation of the mTOR pathway and can be synergistically targeted with rapamycin and metformin. Pflügers Arch. Eur. J. Physiol. 2013, 466, 1591–1604. [Google Scholar] [CrossRef] [PubMed]
- Leonhard, W.N.; Song, X.; Kanhai, A.A.; Iliuta, I.-A.; Bozovic, A.; Steinberg, G.R.; Peters, D.J.; Pei, Y. Salsalate, but not metformin or canagliflozin, slows kidney cyst growth in an adult-onset mouse model of polycystic kidney disease. EBioMedicine 2019, 47, 436–445. [Google Scholar] [CrossRef]
- Menezes, L.F.; Zhou, F.; Patterson, A.D.; Piontek, K.B.; Krausz, K.W.; Gonzalez, F.J.; Germino, G.G. Network Analysis of a Pkd1-Mouse Model of Autosomal Dominant Polycystic Kidney Disease Identifies HNF4α as a Disease Modifier. PLoS Genet. 2012, 8, e1003053. [Google Scholar] [CrossRef]
- Hong, Y.H.; Varanasi, U.S.; Yang, W.; Leff, T. AMP-activated Protein Kinase Regulates HNF4α Transcriptional Activity by Inhibiting Dimer Formation and Decreasing Protein Stability. J. Boil. Chem. 2003, 278, 27495–27501. [Google Scholar] [CrossRef]
- Dankel, S.N.; Hoang, T.; Flågeng, M.H.; Sagen, J.V.; Mellgren, G. cAMP-mediated regulation of HNF-4α depends on the level of coactivator PGC-1α. Biochim. et Biophys. Acta (BBA)-Bioenerg. 2010, 1803, 1013–1019. [Google Scholar] [CrossRef]
- Adamson, A.W.; Suchankova, G.; Rufo, C.; Nakamura, M.T.; Terán-García, M.; Clarke, S.D.; Gettys, T.W. Hepatocyte nuclear factor-4α contributes to carbohydrate-induced transcriptional activation of hepatic fatty acid synthase. Biochem. J. 2006, 399, 285–295. [Google Scholar] [CrossRef]
- Rhee, J.; Ge, H.; Yang, W.; Fan, M.; Handschin, C.; Cooper, M.; Lin, J.; Li, C.; Spiegelman, B.M. Partnership of PGC-1α and HNF4α in the Regulation of Lipoprotein Metabolism. J. Boil. Chem. 2006, 281, 14683–14690. [Google Scholar] [CrossRef]
- Saxton, R.A.; Sabatini, D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell 2017, 168, 960–976. [Google Scholar] [CrossRef] [PubMed]
- Simon, N.; Hertig, A. Alteration of Fatty Acid Oxidation in Tubular Epithelial Cells: From Acute Kidney Injury to Renal Fibrogenesis. Front. Med. 2015, 2. [Google Scholar] [CrossRef] [PubMed]
- Houten, S.M.; Violante, S.; Ventura, F.; Wanders, R.J.A. The Biochemistry and Physiology of Mitochondrial Fatty Acid β-Oxidation and Its Genetic Disorders. Annu. Rev. Physiol. 2016, 78, 23–44. [Google Scholar] [CrossRef] [PubMed]
- Hackl, A.; Mehler, K.; Gottschalk, I.; Vierzig, A.; Eydam, M.; Hauke, J.; Beck, B.B.; Liebau, M.C.; Ensenauer, R.; Weber, L.T.; et al. Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease—different clinical entities and comparable perinatal renal abnormalities. Pediatr. Nephrol. 2017, 32, 791–800. [Google Scholar] [CrossRef] [PubMed]
- Menezes, L.F.; Lin, C.-C.; Zhou, F.; Germino, G.G. Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease. EBioMedicine 2016, 5, 183–192. [Google Scholar] [CrossRef] [PubMed]
- Lakhia, R.; Yheskel, M.; Flaten, A.; Quittner-Strom, E.B.; Holland, W.L.; Patel, V. PPARα agonist fenofibrate enhances fatty acid β-oxidation and attenuates polycystic kidney and liver disease in mice. Am. J. Physiol. Physiol. 2018, 314, F122–F131. [Google Scholar] [CrossRef] [PubMed]
- Yoshihara, D.; Kugita, M.; Yamaguchi, T.; Aukema, H.M.; Kurahashi, H.; Morita, M.; Hiki, Y.; Calvet, J.P.; Wallace, D.P.; Toyohara, T.; et al. Global Gene Expression Profiling in PPAR-γ Agonist-Treated Kidneys in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease. PPAR Res. 2012, 2012, 1–10. [Google Scholar] [CrossRef]
- Batisse-Lignier, M.; Sahut-Barnola, I.; Tissier, F.; Dumontet, T.; Mathieu, M.; Drelon, C.; Pointud, J.-C.; Damon-Soubeyrand, C.; Marceau, G.; Kemeny, J.-L.; et al. P53/Rb inhibition induces metastatic adrenocortical carcinomas in a preclinical transgenic model. Oncogene 2017, 36, 4445–4456. [Google Scholar] [CrossRef]
- Zhou, X.; Fan, L.X.; Sweeney, W.E.; Denu, J.M.; Avner, E.D.; Li, X. Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. J. Clin. Investig. 2013, 123, 3084–3098. [Google Scholar] [CrossRef]
- Li, X. SIRT1 and energy metabolism. Acta Biochim. et Biophys. Sin. 2012, 45, 51–60. [Google Scholar] [CrossRef]
- Locasale, J.W.; Cantley, L.C. Metabolic Flux and the Regulation of Mammalian Cell Growth. Cell Metab. 2011, 14, 443–451. [Google Scholar] [CrossRef] [PubMed]
- Hildebrandt, F.; Benzing, T.; Katsanis, N. Ciliopathies. N. Engl. J. Med. 2011, 364, 1533–1543. [Google Scholar] [CrossRef] [PubMed]
- Habbig, S.; Liebau, M.C. Ciliopathies - from rare inherited cystic kidney diseases to basic cellular function. Mol. Cell. Pediatr. 2015, 2, 1–6. [Google Scholar] [CrossRef]
- Boehlke, C.; Kotsis, F.; Patel, V.; Braeg, S.; Voelker, H.; Bredt, S.; Beyer, T.; Janusch, H.; Hamann, C.; Gödel, M.; et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nature 2010, 12, 1115–1122. [Google Scholar] [CrossRef]
- Warner, G.; Hein, K.Z.; Nin, V.; Edwards, M.; Chini, C.C.; Hopp, K.; Harris, P.C.; Torres, V.E.; Chini, E.N. Food Restriction Ameliorates the Development of Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2015, 27, 1437–1447. [Google Scholar] [CrossRef]
- Kipp, K.R.; Rezaei, M.; Lin, L.; Dewey, E.C.; Weimbs, T. A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease. Am. J. Physiol. Physiol. 2016, 310, F726–F731. [Google Scholar] [CrossRef] [PubMed]
- Bordone, L.; Guarente, L. Calorie restriction, SIRT1 and metabolism: Understanding longevity. Nat. Rev. Mol. Cell Boil. 2005, 6, 298–305. [Google Scholar] [CrossRef] [PubMed]
- Mair, W.B.; Dillin, A. Aging and Survival: The Genetics of Life Span Extension by Dietary Restriction. Annu. Rev. Biochem. 2008, 77, 727–754. [Google Scholar] [CrossRef] [PubMed]
- Nowak, K.L.; You, Z.; Gitomer, B.; Brosnahan, G.; Torres, V.E.; Chapman, A.B.; Perrone, R.D.; Steinman, T.I.; Abebe, K.Z.; Rahbari-Oskoui, F.F.; et al. Overweight and Obesity Are Predictors of Progression in Early Autosomal Dominant Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2017, 29, 571–578. [Google Scholar] [CrossRef]
- Torres, J.A.; Kruger, S.L.; Broderick, C.; Amarlkhagva, T.; Agrawal, S.; Dodam, J.R.; Mrug, M.; Lyons, L.A.; Weimbs, T. Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease. Cell Metab. 2019, 30, 1007–1023.e5. [Google Scholar] [CrossRef]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Haumann, S.; Müller, R.-U.; Liebau, M.C. Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment. Int. J. Mol. Sci. 2020, 21, 6093. https://doi.org/10.3390/ijms21176093
Haumann S, Müller R-U, Liebau MC. Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment. International Journal of Molecular Sciences. 2020; 21(17):6093. https://doi.org/10.3390/ijms21176093
Chicago/Turabian StyleHaumann, Sophie, Roman-Ulrich Müller, and Max C. Liebau. 2020. "Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment" International Journal of Molecular Sciences 21, no. 17: 6093. https://doi.org/10.3390/ijms21176093
APA StyleHaumann, S., Müller, R.-U., & Liebau, M. C. (2020). Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment. International Journal of Molecular Sciences, 21(17), 6093. https://doi.org/10.3390/ijms21176093