Free fatty acids cause podocytes dysfunction and inflammation

Submitted: July 19, 2023
Accepted: November 9, 2023
Published: December 4, 2023
Abstract Views: 488
PDF: 149
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

The mechanisms underlying obesity-related kidney disease are not well understood. Growing evidence suggests that free fatty acids (FFAs), a cause of oxidative stress, play an important role in obesity and its related complications. So, we decided to investigate, in a human-conditioned immortalized podocyte cell line, the capacity of physiopathological concentrations of 27nM of nonconjugated palmitate to induce intracellular reactive oxygen species (ROS) production, podocytes endoplasmic reticulum (ER) stress, podocytes inflammation, and mitochondrial dysfunction. A conditionally immortalized human podocyte cell line was exposed to different percentages of palmitate conjugated to bovine serum albumin (BSA) for 24h. We observed that palmitate, at the same concentrations seen in obese patients, caused overproduction of ROS in human podocytes and this oxidative stress induces dysfunctions in podocytes like inflammation and changes in profibrotic and lipotoxic markers. High-mobility group box 1 (HMGB1) is likely known to be a major mediator of ROS damaging effects, as its pharmacological inhibition prevents all ROS effects on podocytes. Our study shows how, in podocytes, an unbounded fraction of 27nM of palmitate can induce dysfunctions similar to that observed in obesity-related glomerulopathy (ORG). These results could contribute to elucidating underlying mechanisms contributing to the ORG pathogenesis.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:766-81. DOI: https://doi.org/10.1016/S0140-6736(14)60460-8
Manna P, Jain SK. Obesity, oxidative stress, adipose tissue dysfunction, and the associated health risks: causes and therapeutic strategies. Metab Syndr Relat Disord 2015;13: 423-44. DOI: https://doi.org/10.1089/met.2015.0095
Wang Y, Chen X, Song Y, et al. Association between obesity and kidney disease: a systematic review and meta-analysis. Kidney Int 2008;73:19-33. DOI: https://doi.org/10.1038/sj.ki.5002586
Giardino I, D'Apolito M, Brownlee M, et al. Vascular toxicity of urea, a new "old player" in the pathogenesis of chronic renal failure induced cardiovascular diseases. Turk Pediatri Ars 2017;52:187-93 DOI: https://doi.org/10.5152/TurkPediatriArs.2017.6314
Morgese MG, Bove M, Di Cesare Mannelli L, et al. Precision medicine in Alzheimer’s disease: investigating comorbid common biological substrates in the rat model of amyloid beta-induced toxicity. Front Pharm 2022;12:799561. DOI: https://doi.org/10.3389/fphar.2021.799561
D'Apolito M, Du X, Pisanelli D, et al. Urea-induced ROS cause endothelial dysfunction in chronic renal failure. Atherosclerosis 2015;239:393-400 DOI: https://doi.org/10.1016/j.atherosclerosis.2015.01.034
Felizardo RJ, da Silva MB, Aguiar CF, Câmara NO. Obesity in kidney disease: a heavyweight opponent. World J Nephrol 2014;3:50-63 DOI: https://doi.org/10.5527/wjn.v3.i3.50
Shoji T, Emoto M, Kawagishi T, et al. Atherogenic lipoprotein changes in diabetic nephropathy. Atherosclerosis 2001;156:425-33 DOI: https://doi.org/10.1016/S0021-9150(00)00673-0
Griffin KA, Kramer H, Bidani AK. Adverse renal consequences of obesity. Am J Physiol Renal Physiol 2008;294:F685-96 DOI: https://doi.org/10.1152/ajprenal.00324.2007
Xu S, Nam SM, Kim JH, et al. Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress. Cell Death Dis 2015;6:e1976. DOI: https://doi.org/10.1038/cddis.2015.331
Morgese MG, Schiavone S, Bove M et al. N-3 PUFA prevent oxidative stress in a rat model of beta-amyloid-induced toxicity. Pharmaceuticals 2021;14:339. DOI: https://doi.org/10.3390/ph14040339
Szeto HH, Liu S, Soong Y, et al. Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury. Kidney Int 2016;90:997-1011. DOI: https://doi.org/10.1016/j.kint.2016.06.013
D'Apolito M, Colia AL, Lasalvia M, et al. Urea-induced ROS accelerate senescence in endothelial progenitor cells. Atherosclerosis 2017;263:127-36. DOI: https://doi.org/10.1016/j.atherosclerosis.2017.06.028
Nagata M. Podocyte injury and its consequences. Kidney Int 2016;89:1221-30. DOI: https://doi.org/10.1016/j.kint.2016.01.012
Wei L, Li Y, Yu Y et al. Obesity-related glomerulopathy: from mechanism to therapeutic target. Diabetes Metab Syndr Obes 2021;14:4371-80. DOI: https://doi.org/10.2147/DMSO.S334199
Vandanmagsar B, Youm Y-H, Ravussin A et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011;17:179-88. DOI: https://doi.org/10.1038/nm.2279
Cnop M. Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes. Biochem Soc Trans 2008;36:348-52. DOI: https://doi.org/10.1042/BST0360348
Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME. The c-Jun N-terminal kinase mediates the induction of oxidative stress and insulin resistance by palmitate and toll-like receptor 2 and 4 ligands in 3T3-L1 adipocytes. Horm Metab Res 2009;41:523-30. DOI: https://doi.org/10.1055/s-0029-1202852
Tsushima K, Bugger H, Wende A, et al. Mitochondrial reactive oxygen species in lipotoxic hearts induces post-translational modifications of AKAP121, DRP1 and OPA1 that promote mitochondrial fission. Circ Res 2018;122:58-73. DOI: https://doi.org/10.1161/CIRCRESAHA.117.311307
Chen Q, Guan X, Zuo X et al. The role of high mobility group box 1 (HMGB1) in the pathogenesis of kidney diseases. Acta Pharm Sin B 2016;6:183-8. DOI: https://doi.org/10.1016/j.apsb.2016.02.004
Stamps AC, Davies SC, Burman J, O'Hare MJ. Analysis of proviral integration in human mammary epithelial cell lines immortalized by retroviral infection with a temperature-sensitive SV40 T-antigen construct. Int J Cancer 1994;57:865-74. DOI: https://doi.org/10.1002/ijc.2910570616
Saleem MA, Ni L, Witherden I, et al. Co-localization of nephrin, podocin and the actin cytoskeleton: evidence for a role in podocyte foot process formation. Am J Pathol 2002;161:1459-66 DOI: https://doi.org/10.1016/S0002-9440(10)64421-5
Huber AH, Kleinfeld AM. Unbound free fatty acid profiles in human plasma and the unexpected absence of unbound palmitoleate. Lipid Res 2017;58:578-85. DOI: https://doi.org/10.1194/jlr.M074260
Oliveira AF, Cunha DA, Ladriere L, et al. In vitro use of free fatty acids bound to albumin: A comparison of protocols. Biotechniques 2015;58:228-33. DOI: https://doi.org/10.2144/000114285
Alsabeeh N, Chausse B, Kakimoto PA, et al. Cell culture models of fatty acid overload: problems and solutions. Biochim Biophys Acta Mol Cell Biol Lipids 2018;1863:143-51 DOI: https://doi.org/10.1016/j.bbalip.2017.11.006
D'Apolito M, Colia AL, Manca E et al. Urea memory: transient cell exposure to urea causes persistent mitochondrial ROS production and endothelial dysfunction. Toxins 2018;10:410 DOI: https://doi.org/10.3390/toxins10100410
D'Apolito M, Du X, Zong H et al. Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure J Clin Invest 2010;120:203-13. DOI: https://doi.org/10.1172/JCI37672
Mollica L, De Marchis F, Spitaleri A, et al. Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities. Chem Boil 2007;14:431-41. DOI: https://doi.org/10.1016/j.chembiol.2007.03.007
Hyeoncheol K, Xiang X. Detection of total reactive oxygen species in adherent cells by 2’,7’-dichlorodihydrofluorescein diacetate staining. J Vis Exp 2020;160:10.3791-60682.
Nolan T, Hands R, Bustin S. Quantification of mRNA using real-time RT-PCR. Nat Protoc 2006;1:1559-82 DOI: https://doi.org/10.1038/nprot.2006.236
Aoyama T, Paik Y-H, Watanabe S, et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 2012;2316-27. DOI: https://doi.org/10.1002/hep.25938
Yuan H, Zhang X, Huang X, et al. NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways. PloS One 2010;5:e15726. DOI: https://doi.org/10.1371/journal.pone.0015726
Spector AA. Fatty acid binding to plasma albumin. J Lipid Res 1975;16:165-79. DOI: https://doi.org/10.1016/S0022-2275(20)36723-7
Jiang XS, Chen X, Wan J, et al. Autophagy protects against palmitic acid-induced apoptosis in podocytes in vitro. Sci Rep 2017;22;7:42764. DOI: https://doi.org/10.1038/srep42764
Nolan E, O’Meara YM, Godson C. Lipid mediators of inflammation in obesity-related glomerulopathy. Nephrol Dial Transplant 2013;28:iv22-9. DOI: https://doi.org/10.1093/ndt/gft392
Ferré P, Foufelle F. SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res 2007;68:72-82. DOI: https://doi.org/10.1159/000100426
Zhang H, Zhang R, Chen J et al. High mobility group box1 inhibitor glycyrrhizic acid attenuates kidney injury in streptozotocin-induced diabetic rats. Kidney Blood Press Res 2017;42:894-904. DOI: https://doi.org/10.1159/000485045
Pastorino G, Cornara L, Soares S, et al. Liquorice (Glycyrrhiza glabra): a phytochemical and pharmacological review. Phytother Res 2018;32:2323-39. DOI: https://doi.org/10.1002/ptr.6178
Qiang X, Peng Y, Wang Z et al. Synthesis of glycyrrhizin analogues as HMGB1 inhibitors and their activity against sepsis in acute kidney injury. Eur J Med Chem 2023;259:115696. DOI: https://doi.org/10.1016/j.ejmech.2023.115696

How to Cite

Colia, A. L., D’Apolito, M., Ranaldi, A., D’Ambrosio, M. F., Giardino, I., & Maffione, A. B. (2023). Free fatty acids cause podocytes dysfunction and inflammation. Journal of Biological Research - Bollettino Della Società Italiana Di Biologia Sperimentale, 96(2). https://doi.org/10.4081/jbr.2023.11596