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Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities
Open accessAbstract
Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.
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“In addition, parenchymal lipid deposition may induce lipotoxicity (50) through the formation of toxic metabolites including ceramides and diacylglyceride that hamper the function of multiple kidney cell types, including podocytes (51).”
From GLP-1 agonists in the treatment of chronic kidney disease in type 2 diabetes and obesity (2025) · cites this paper as [50]
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Metadata
- Authors
- Opazo-Ríos, L., Mas, S., Marín-Royo, G., Mezzano, S., Gómez-Guerrero, C., Moreno, J. A., & Egido, J.
- Affiliations
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
- Austral University of Chile (CL)
- Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
- Corresponding author
- Mas, Sebastián
- Moreno, Juan Antonio
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2020-04-10
- Volume
- 21
- Issue
- 7
- Pages
- 2632
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7177360
- OpenAlex
- W3015924535
- Cited by
- 363
- References
- 257
- Citations by year
- 2026: 61 · 2025: 68 · 2024: 72 · 2023: 66 · 2022: 61 · 2021: 27 · 2020: 6
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion)
- Biblos-e Archivo (Universidad Autónoma de Madrid) (submittedVersion, public-domain)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by-sa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Universidad de Córdoba Insitutional Repository (Universidad de Córdoba) (submittedVersion, cc-by)
- Hispana (submittedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
- Funders
- Instituto de Salud Carlos III (PI17/01495, PI17/00130, SAF2015-63696-R)
- Ministerio de Ciencia e Innovación (DTS17/00203, RTI2018-098788-B-100, DTS19/00093, RYC-2017-22369)
- Fondo Nacional de Desarrollo Científico y Tecnológico (1160465)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- lipotoxicity, diabetic nephropathy, ectopic fat deposition, type 2 diabetes, insulin resistance, hyperinsulinemia, free fatty acids, lipid metabolism, podocyte injury, tubular damage, mesangial cell proliferation, endothelial activation, foam cells, inflammation, oxidative stress, mitochondrial dysfunction, cell death, treatment options
- MeSH terms
- Clinical Decision-Making, Adipose Tissue, Animals, Diabetic Nephropathies, Disease Susceptibility, Fatty Acids, Nonesterified, Glycogen, Humans, Kidney, Mitochondria, Obesity, Prognosis, Signal Transduction, Biomarkers, Disease Management, Dyslipidemias, Lipid Metabolism
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