Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells
Abstract
:1. Introduction
2. Materials and Methods
2.1. Nanoliposome Preparation and Quantification
2.2. Cell Culture
2.3. Lipid Vesicle Imaging
2.4. Monitoring Mitochondrial Abundance and Function
2.5. Fluorescence Microscopy/Imaging
2.6. Multiplex Protein Quantification
2.7. Multiplex mRNA Quantification
2.8. Protein Phosphorylation Array
2.9. Statistical Analysis
3. Results
3.1. The Physicochemical Characteristics of SUVs and Farnesol-SUVs
3.2. Uptake of SUVs and Farnesol-SUVs by RPTECs
3.3. SUVs and Farnesol-SUVs Do Not Affect Mitochondrial Abundance or Activity in RPTECs
3.4. Farnesol-SUVs Inhibit TNF-α/IL-1β-Induced Expression of Inflammatory Proteins in RPTECs
3.5. Farnesol-SUVs Inhibits TNF-α/IL-1β-Induced mRNA Expression of Inflammatory Genes in RPTECs
3.6. Farnesol-SUVs Inhibits the Phosphorylation of Signaling Proteins in RPTECs
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Qu, L.; Jiao, B. The Interplay between Immune and Metabolic Pathways in Kidney Disease. Cells 2023, 12, 1584. [Google Scholar] [CrossRef] [PubMed]
- der Hauwaert, V.; Savary, G.; Gnemmi, V.; Glowacki, F.; Pottier, N.; Bouillez, A.; Maboudou, P.; Zini, L.; Leroy, X.; Cauffiez, C.; et al. Isolation and Characterization of a Primary Proximal Tubular Epithelial Cell Model from Human Kidney by Cd10/Cd13 Double Labeling. PLoS ONE 2013, 8, e66750. [Google Scholar] [CrossRef] [PubMed]
- Smith, P.L.; Buffington, D.A.; Humes, H.D. Kidney Epithelial Cells. Methods Enzym. 2006, 419, 194–207. [Google Scholar]
- Cantaluppi, V.; Quercia, A.D.; Dellepiane, S.; Ferrario, S.; Camussi, G.; Biancone, L. Interaction between Systemic Inflammation and Renal Tubular Epithelial Cells. Nephrol. Dial. Transpl. 2014, 29, 2004–2011. [Google Scholar] [CrossRef] [PubMed]
- Chatterjee, P.K.; Hawksworth, G.M.; McLay, J.S. Cytokine-Stimulated Nitric Oxide Production in the Human Renal Proximal Tubule and Its Modulation by Natriuretic Peptides: A Novel Immunomodulatory Mechanism? Exp. Nephrol. 1999, 7, 438–448. [Google Scholar] [CrossRef] [PubMed]
- Ye, H.Y.; Song, Y.L.; Ye, W.T.; Xiong, C.X.; Li, J.M.; Miao, J.H.; Shen, W.W.; Li, X.L.; Zhou, L.L. Serum Granulosa Cell-Derived Tnf-Alpha Promotes Inflammation and Apoptosis of Renal Tubular Cells and Pcos-Related Kidney Injury through Nf-Kappab Signaling. Acta Pharmacol. Sin. 2023, 44, 2432–2444. [Google Scholar] [CrossRef] [PubMed]
- Koch, B.; Fuhrmann, D.C.; Schubert, R.; Geiger, H.; Speer, T.; Baer, P.C. Gliflozins Have an Anti-Inflammatory Effect on Renal Proximal Tubular Epithelial Cells in a Diabetic and Inflammatory Microenvironment in Vitro. Int. J. Mol. Sci. 2023, 24, 1811. [Google Scholar] [CrossRef]
- Hu, Y.; Sun, Y.A.; Shi, J.Q.; Xu, J. High-Fat Diet Caused Renal Damage in Apoe(−/−) Mice Via the Activation of Rage-Mediated Inflammation. Toxicol. Res. 2021, 10, 1171–1176. [Google Scholar]
- Nauta, A.J.; de Haij, S.; Bottazzi, B.; Mantovani, A.; Borrias, M.C.; Aten, J.; Rastaldi, M.P.; Daha, M.R.; van Kooten, C.; Roos, A. Human Renal Epithelial Cells Produce the Long Pentraxin Ptx3. Kidney Int. 2005, 67, 543–553. [Google Scholar] [CrossRef]
- Ott, L.W.; Resing, K.A.; Sizemore, A.W.; Heyen, J.W.; Cocklin, R.R.; Pedrick, N.M.; Woods, H.C.; Chen, J.Y.; Goebl, M.G.; Witzmann, F.A.; et al. Tumor Necrosis Factor-Alpha- and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information. J. Proteome Res. 2007, 6, 2176–2185. [Google Scholar] [CrossRef]
- Fruman, D.A. Regulatory Subunits of Class Ia Pi3k. Curr. Top. Microbiol. Immunol. 2010, 346, 225–244. [Google Scholar] [PubMed]
- Fruman, D.A.; Chiu, H.; Hopkins, B.D.; Bagrodia, S.; Cantley, L.C.; Abraham, R.T. The Pi3k Pathway in Human Disease. Cell 2017, 170, 605–635. [Google Scholar] [CrossRef] [PubMed]
- Jung, Y.Y.; Hwang, S.T.; Sethi, G.; Fan, L.; Arfuso, F.; Ahn, K.S. Potential Anti-Inflammatory and Anti-Cancer Properties of Farnesol. Molecules 2018, 23, 2827. [Google Scholar] [CrossRef]
- Ku, C.-M.; Lin, J.-Y. Farnesol, a Sesquiterpene Alcohol in Herbal Plants, Exerts Anti-Inflammatory and Antiallergic Effects on Ovalbumin-Sensitized and -Challenged Asthmatic Mice. Evid. Based Complement Altern. Med. 2015, 2015, 387357. [Google Scholar] [CrossRef] [PubMed]
- Doyle, W.J.; Walters, D.; Shi, X.; Hoffman, K.; Magori, K.; Roullet, J.-B.; Ochoa-Repáraz, J. Farnesol Brain Transcriptomics in Cns Inflammatory Demyelination. Clin. Immunol. 2023, 255, 109752. [Google Scholar] [CrossRef] [PubMed]
- Ghosh, S.; Howe, N.; Volk, K.; Tati, S.; Nickerson, K.W.; Petro, T.M. Candida Albicans Cell Wall Components and Farnesol Stimulate the Expression of Both Inflammatory and Regulatory Cytokines in the Murine Raw264.7 Macrophage Cell Line. FEMS Immunol. Med. Microbiol. 2010, 60, 63–73. [Google Scholar] [CrossRef] [PubMed]
- Nsairat, K.D.; Sayed, U.; Odeh, F.; Al Bawab, A.; Alshaer, W. Liposomes: Structure, Composition, Types, and Clinical Applications. Heliyon 2022, 8, e09394. [Google Scholar] [CrossRef]
- Mückter, E.; Lozoya, M.; Müller, A.; Weissig, V.; Nourbakhsh, M. Farnesol-Loaded Nanoliposomes Inhibit Inflammatory Gene Expression in Primary Human Skeletal Myoblasts. Biology 2022, 11, 701. [Google Scholar] [CrossRef]
- Danaei, M.; Dehghankhold, M.; Ataei, S.; Hasanzadeh Davarani, F.; Javanmard, R.; Dokhani, A.; Khorasani, S.; Mozafari, M.R. Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems. Pharmaceutics 2018, 10, 57. [Google Scholar] [CrossRef]
- Jiang, X.S.; Cai, M.Y.; Li, X.J.; Zhong, Q.; Li, M.L.; Xia, Y.F.; Shen, Q.; Du, X.G.; Gan, H. Activation of the Nrf2/Are Signaling Pathway Protects against Palmitic Acid-Induced Renal Tubular Epithelial Cell Injury by Ameliorating Mitochondrial Reactive Oxygen Species-Mediated Mitochondrial Dysfunction. Front Med. 2022, 9, 939149. [Google Scholar] [CrossRef]
- Phengpol, N.; Thongnak, L.; Lungkaphin, A. The Programming of Kidney Injury in Offspring Affected by Maternal Overweight and Obesity: Role of Lipid Accumulation, Inflammation, Oxidative Stress, and Fibrosis in the Kidneys of Offspring. J. Physiol. Biochem. 2023, 79, 1–17. [Google Scholar] [CrossRef] [PubMed]
- Cattley, R.T.; Lee, M.; Boggess, W.C.; Hawse, W.F. Transforming Growth Factor Beta (Tgf-Beta) Receptor Signaling Regulates Kinase Networks and Phosphatidylinositol Metabolism During T-Cell Activation. J. Biol. Chem. 2020, 295, 8236–8251. [Google Scholar] [CrossRef] [PubMed]
- Clayton, N.S.; Fox, M.; Vicenté-Garcia, J.J.; Schroeder, C.M.; Littlewood, T.D.; Wilde, J.I.; Krishnan, K.; Brown, M.J.; Crafter, C.; Mott, H.R.; et al. Assembly of Nuclear Dimers of Pi3k Regulatory Subunits Is Regulated by the Cdc42-Activated Tyrosine Kinase Ack. J. Biol. Chem. 2022, 298, 101916. [Google Scholar] [CrossRef] [PubMed]
- Armbrust, T.; Millis, M.P.; Alvarez, M.L.; Saremi, A.; DiStefano, J.K.; Nourbakhsh, M. Cxcl4l1 Promoter Polymorphisms Are Associated with Improved Renal Function in Type 1 Diabetes. J. Immunol. 2019, 202, 912–919. [Google Scholar] [CrossRef] [PubMed]
- Koch, I.; Büttner, B. Computational Modeling of Signal Transduction Networks without Kinetic Parameters: Petri Net Approaches. Am. J. Physiol. Physiol. 2023, 324, C1126–C1140. [Google Scholar] [CrossRef]
- Sanagawa, A.; Hotta, Y.; Sezaki, R.; Tomita, N.; Kataoka, T.; Furukawa-Hibi, Y.; Kimura, K. Effect of Replicative Senescence on the Expression and Function of Transporters in Human Proximal Renal Tubular Epithelial Cells. Biol. Pharm. Bull. 2022, 45, 1636–1643. [Google Scholar] [CrossRef] [PubMed]
- Nagawa, D.; Shimada, M.; Nakata, M.; Narita-Kinjo, I.; Fujita, T.; Murakami, R.; Nakamura, N.; Tomita, H. Hypoxia-Inducible Factor-1alpha Suppresses the Innate Immune Response in Cultured Human Proximal Tubular Cells. Vivo 2023, 37, 2437–2446. [Google Scholar] [CrossRef]
- Chan, J.W.; Neo, C.W.Y.; Ghosh, S.; Choi, H.; Lim, S.C.; Tai, E.S.; Teo, A.K.K. Hnf1a Binds and Regulates the Expression of Slc51b to Facilitate the Uptake of Estrone Sulfate in Human Renal Proximal Tubule Epithelial Cells. Cell Death Dis. 2023, 14, 302. [Google Scholar] [CrossRef]
- Bae, J.-H.; Jo, A.; Cho, S.C.; Lee, Y.-I.; Kam, T.-I.; You, C.-L.; Jeong, H.-J.; Kim, H.; Jeong, M.-H.; Jeong, Y.; et al. Farnesol Prevents Aging-Related Muscle Weakness in Mice through Enhanced Farnesylation of Parkin-Interacting Substrate. Sci. Transl. Med. 2023, 15, eabh3489. [Google Scholar] [CrossRef]
- Wang, Y.Y.; Liu, Y.Y.; Li, J.; Zhang, Y.Y.; Ding, Y.F.; Peng, Y.R. Gualou Xiebai Decoction Ameliorates Cardiorenal Syndrome Type Ii by Regulation of Pi3k/Akt/Nf-Kappab Signalling Pathway. Phytomedicine 2023, 123, 155172. [Google Scholar] [CrossRef]
- Han, Y.; Liu, X.; Shang, J.; Li, N.; Zhang, C.; Li, Y.; Zheng, J. Bioinformatics-Based Analysis of Core Genes and Pathway Enrichment in Early Diabetic Nephropathy. Cell Mol. Biol. 2023, 69, 51–56. [Google Scholar] [PubMed]
- Yang, L.; Yuan, S.; Wang, R.; Guo, X.; Xie, Y.; Wei, W.; Tang, L. Exploring the Molecular Mechanism of Berberine for Treating Diabetic Nephropathy Based on Network Pharmacology. Int. Immunopharmacol. 2023, 126, 111237. [Google Scholar] [CrossRef] [PubMed]
- Wei, Y.; Zhou, J.; Yu, H.; Jin, X. Akt Phosphorylation Sites of Ser473 and Thr308 Regulate Akt Degradation. Biosci. Biotechnol. Biochem. 2018, 83, 429–435. [Google Scholar] [CrossRef]
- Torres, A.N.B.; Melchers, R.C.; Van Grieken, L.; Out-Luiting, J.J.; Mei, H.; Agaser, C.; Kuipers, T.B.; Quint, K.D.; Willemze, R.; Vermeer, M.H.; et al. Whole-Genome Profiling of Primary Cutaneous Anaplastic Large Cell Lymphoma. Haematologica 2021, 107, 1619–1632. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; He, Z.; Zhang, J.; Han, Y. Identification of Crucial Noncoding Rnas and Mrnas in Hypertrophic Scars Via Rna Sequencing. FEBS Open Bio. 2021, 11, 1673–1684. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Ma, C.; Ji, J.; Xu, W.; Shao, Q.; Liao, X.; Li, Y.; Cheng, F.; Wang, Q. Identification of Potential Regulating Effect of Baicalin on Nfkappab/Ccl2/Ccr2 Signaling Pathway in Rats with Cerebral Ischemia by Antibody-Based Array and Bioinformatics Analysis. J. Ethnopharmacol. 2022, 284, 114773. [Google Scholar]
- Kuhnel, F.; Zender, L.; Paul, Y.; Tietze, M.K.; Trautwein, C.; Manns, M.; Kubicka, S. Nfkappab Mediates Apoptosis through Transcriptional Activation of Fas (Cd95) in Adenoviral Hepatitis. J. Biol. Chem. 2000, 275, 6421–6427. [Google Scholar] [CrossRef]
- Lupton, S.D.; Gimpel, S.; Jerzy, R.; Brunton, L.L.; Hjerrild, K.A.; Cosman, D.; Goodwin, R.G. Characterization of the Human and Murine Il-7 Genes. J. Immunol. 1990, 144, 3592–3601. [Google Scholar] [CrossRef]
- Weitzmann, M.N.; Cenci, S.; Rifas, L.; Brown, C.; Pacifici, R. Interleukin-7 Stimulates Osteoclast Formation by up-Regulating the T-Cell Production of Soluble Osteoclastogenic Cytokines. Blood 2000, 96, 1873–1878. [Google Scholar] [CrossRef]
- Gluba-Sagr, A.; Franczyk, B.; Rysz-Górzyńska, M.; Ławiński, J.; Rysz, J. The Role of Mirna in Renal Fibrosis Leading to Chronic Kidney Disease. Biomedicines 2023, 11, 2358. [Google Scholar] [CrossRef]
- Nano, J.; Schöttker, B.; Lin, J.-S.; Huth, C.; Ghanbari, M.; Garcia, P.M.; Maalmi, H.; Karrasch, S.; Koenig, W.; Rothenbacher, D.; et al. Novel Biomarkers of Inflammation, Kidney Function and Chronic Kidney Disease in the General Population. Nephrol. Dial. Transplant. 2021, 37, 1916–1926. [Google Scholar] [CrossRef] [PubMed]
- Ciceri, P.; Bono, V.; Magagnoli, L.; Sala, M.; Monforte, A.D.; Galassi, A.; Barassi, A.; Marchetti, G.; Cozzolino, M. Cytokine and Chemokine Retention Profile in Covid-19 Patients with Chronic Kidney Disease. Toxins 2022, 14, 673. [Google Scholar] [CrossRef] [PubMed]
- Colombo, M.; McGurnaghan, S.J.; Blackbourn, L.A.K.; Dalton, R.N.; Dunger, D.; Bell, S.; Petrie, J.R.; Green, F.; MacRury, S.; McKnight, J.A.; et al. Comparison of Serum and Urinary Biomarker Panels with Albumin/Creatinine Ratio in the Prediction of Renal Function Decline in Type 1 Diabetes. Diabetologia 2020, 63, 788–798. [Google Scholar] [CrossRef] [PubMed]
- Hao, J.; Wei, Q.; Mei, S.; Li, L.; Su, Y.; Mei, C.; Dong, Z. Induction of Microrna-17-5p by P53 Protects against Renal Ischemia-Reperfusion Injury by Targeting Death Receptor 6. Kidney Int. 2016, 91, 106–118. [Google Scholar] [CrossRef] [PubMed]
- Neilson, E.G. Mechanisms of Disease: Fibroblasts—A New Look at an Old Problem. Nat. Clin. Pr. Nephrol. 2006, 2, 101–108. [Google Scholar] [CrossRef]
- Tampe, D.; Zeisberg, M. Potential Approaches to Reverse or Repair Renal Fibrosis. Nat. Rev. Nephrol. 2014, 10, 226–237. [Google Scholar] [CrossRef]
- Singh, S.; Anshita, D.; Ravichandiran, V. Regulation, and Involvement in Disease. Int. Immunopharmacol. 2021, 101 Pt B, 107598. [Google Scholar] [CrossRef]
- Costa, W.C.; Beltrami, V.A.; Campolina-Silva, G.H.; Queiroz-Junior, C.M.; Florentino, R.M.; Machado, J.R.; Martins, D.G.; Gonçalves, W.A.; Barroso, L.C.; Freitas, K.M.; et al. Therapeutic Treatment with Phosphodiesterase-4 Inhibitors Alleviates Kidney Injury and Renal Fibrosis by Increasing Mmp-9 in a Doxorubicin-Induced Nephrotoxicity Mouse Model. Int. Immunopharmacol. 2023, 115, 109583. [Google Scholar] [CrossRef]
- Ling, Y.H.; Krishnan, S.M.; Chan, C.T.; Diep, H.; Ferens, D.; Chin-Dusting, J.; Kemp-Harper, B.K.; Samuel, C.S.; Hewitson, T.D.; Latz, E.; et al. Anakinra Reduces Blood Pressure and Renal Fibrosis in One Kidney/Doca/Salt-Induced Hypertension. Pharmacol. Res. 2016, 116, 77–86. [Google Scholar] [CrossRef]
- Deng, Y.-J.; Lin, X.-P.; Li, X.-Q.; Lu, P.-F.; Cai, Y.; Liu, L.-L.; Pei, G.-C.; Han, M. Interleukin-7 Is Associated with Clinical and Pathological Activities in Immunoglobulin a Nephropathy and Protects the Renal Proximal Tubule Epithelium from Cellular Fibrosis. Curr. Med. Sci. 2021, 41, 880–887. [Google Scholar] [CrossRef]
Composition | Size by Volume (nm) | Polydispersity Index | |
---|---|---|---|
SUVs | PCsoy (25 mM)/TAP (0.5 mM) | 28.2 ± 1.62 | 0.325 |
Farnesol-SUVs | PCsoy (25 mM)/TAP (0.5 mM)/Farnesol (4 mM) | 31.63 ± 1.97 | 0.268 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 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 (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Müller, A.; Lozoya, M.; Chen, X.; Weissig, V.; Nourbakhsh, M. Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells. Biomedicines 2023, 11, 3322. https://doi.org/10.3390/biomedicines11123322
Müller A, Lozoya M, Chen X, Weissig V, Nourbakhsh M. Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells. Biomedicines. 2023; 11(12):3322. https://doi.org/10.3390/biomedicines11123322
Chicago/Turabian StyleMüller, Aline, Maria Lozoya, Xiaoying Chen, Volkmar Weissig, and Mahtab Nourbakhsh. 2023. "Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells" Biomedicines 11, no. 12: 3322. https://doi.org/10.3390/biomedicines11123322
APA StyleMüller, A., Lozoya, M., Chen, X., Weissig, V., & Nourbakhsh, M. (2023). Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells. Biomedicines, 11(12), 3322. https://doi.org/10.3390/biomedicines11123322