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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.<\/jats:p>","DOI":"10.3390\/ijms21072632","type":"journal-article","created":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T04:45:31Z","timestamp":1586753131000},"page":"2632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":353,"title":["Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3586-3319","authenticated-orcid":false,"given":"Lucas","family":"Opazo-R\u00edos","sequence":"first","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6604-3327","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Mas","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gema","family":"Mar\u00edn-Royo","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Mezzano","sequence":"additional","affiliation":[{"name":"Laboratorio de Nefrolog\u00eda, Facultad de Medicina, Universidad Austral de Chile, 5090000 Valdivia, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-5414","authenticated-orcid":false,"given":"Carmen","family":"G\u00f3mez-Guerrero","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7468-2871","authenticated-orcid":false,"given":"Juan Antonio","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain"},{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, 14004 Cordoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda, 14004 Cordoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Egido","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1194\/jlr.R083915","article-title":"Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles","volume":"59","author":"Verderio","year":"2018","journal-title":"J. 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