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      New insights into renal lipid dysmetabolism in diabetic kidney disease

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          Abstract

          Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs, including the kidney. Research suggests that impaired cholesterol metabolism, increased lipid uptake or synthesis, increased fatty acid oxidation, lipid droplet accumulation and an imbalance in biologically active sphingolipids (such as ceramide, ceramide-1-phosphate and sphingosine-1-phosphate) contribute to the development of diabetic kidney disease (DKD). Currently, the literature suggests that both quality and quantity of lipids are associated with DKD and contribute to increased reactive oxygen species production, oxidative stress, inflammation, or cell death. Therefore, control of renal lipid dysmetabolism is a very important therapeutic goal, which needs to be archived. This article will review some of the recent advances leading to a better understanding of the mechanisms of dyslipidemia and the role of particular lipids and sphingolipids in DKD.

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          Most cited references130

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          Autophagy regulates lipid metabolism.

          The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
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            Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.

            Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.
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              Transcriptome Analysis of Human Diabetic Kidney Disease

              OBJECTIVE Diabetic kidney disease (DKD) is the single leading cause of kidney failure in the U.S., for which a cure has not yet been found. The aim of our study was to provide an unbiased catalog of gene-expression changes in human diabetic kidney biopsy samples. RESEARCH DESIGN AND METHODS Affymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. DKD samples were significant for their racial diversity and decreased glomerular filtration rate (~25–35 mL/min). Stringent statistical analysis, using the Benjamini-Hochberg corrected two-tailed t test, was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. Two different web-based algorithms were used to define differentially regulated pathways. RESULTS We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli, and 330 probesets were commonly differentially expressed in both compartments. Pathway analysis highlighted the regulation of Ras homolog gene family member A, Cdc42, integrin, integrin-linked kinase, and vascular endothelial growth factor signaling in DKD glomeruli. The tubulointerstitial compartment showed strong enrichment for inflammation-related pathways. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in a different set of DKD samples. CONCLUSIONS Our studies have cataloged gene-expression regulation and identified multiple novel genes and pathways that may play a role in the pathogenesis of DKD or could serve as biomarkers.
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                Author and article information

                Contributors
                Journal
                World J Diabetes
                WJD
                World Journal of Diabetes
                Baishideng Publishing Group Inc
                1948-9358
                15 May 2021
                15 May 2021
                : 12
                : 5
                : 524-540
                Affiliations
                Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States. a.mitrofanova@ 123456miami.edu
                Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
                Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
                Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
                Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
                Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
                Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
                Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
                Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
                Author notes

                Author contributions: Mitrofanova A prepared the draft of the manuscript; Burke G, Merscher S and Fornoni A revised the manuscript; Merscher S helped with the figures.

                Supported by the National Institute of Health (Research in Dr. Alessia Fornoni’s laboratory), No. R01DK117599, No. R01DK104753, No. R01CA227493, No. U54DK083912, No. UM1DK100846, and No. U01DK116101; the Miami Clinical Translational Science Institute, No. UL1TR000460; and the Chernowitz Medical Research Foundation (Mitrofanova A and Burke G), No. GR016291.

                Corresponding author: Alla Mitrofanova, PhD, Instructor, Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, 1580 NW 10 th Avenue, Batchelor Bldg, 6 th Floor, Miami, FL 33136, United States. a.mitrofanova@ 123456miami.edu

                Article
                jWJD.v12.i5.pg524
                10.4239/wjd.v12.i5.524
                8107981
                33995842
                b129cdbd-3184-4db2-98e5-3261e99d6530
                ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/

                History
                : 25 January 2021
                : 31 March 2021
                : 26 April 2021
                Categories
                Review

                diabetes,lipids,free fatty acids,atp-binding cassette transporters sub-class a,sterol-o-acyltransferase 1,cd36,sphingolipids,sphingomyelin phosphodiesterase acid-like 3b,diabetic kidney disease

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