Podocyte lipotoxicity in diabetic kidney disease

Nishi, Hiroshi; Nangaku, Masaomi

doi:10.1016/j.kint.2019.07.013

Cited by 18 publications

(12 citation statements)

References 9 publications

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“…Some of the DN explicit physiological pathways, including fatty acid and peroxisomal lipid metabolism, amino acid metabolism, and biological oxidations were among the top enriched ones for the genes in this module. Based on recent findings, alteration in metabolite levels in some pathways, including the TCA cycle, lipids metabolism, amino acids metabolism, and the urea cycle, is strongly associated with DN progression [ 19 – 22 ]. Aberrant levels of metabolites are also linked with oxidative stress and changes in renal hemodynamics.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of diabetic nephropathy expression profile based on weighted gene co-expression network analysis algorithm

2021

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Background Diabetic nephropathy (DN) is the major complication of diabetes mellitus, and leading cause of end-stage renal disease. The underlying molecular mechanism of DN is not yet completely clear. The aim of this study was to analyze a DN microarray dataset using weighted gene co-expression network analysis (WGCNA) algorithm for better understanding of DN pathogenesis and exploring key genes in the disease progression. Methods The identified differentially expressed genes (DEGs) in DN dataset GSE47183 were introduced to WGCNA algorithm to construct co-expression modules. STRING database was used for construction of Protein-protein interaction (PPI) networks of the genes in all modules and the hub genes were identified considering both the degree centrality in the PPI networks and the ranked lists of weighted networks. Gene ontology and Reactome pathway enrichment analyses were performed on each module to understand their involvement in the biological processes and pathways. Following validation of the hub genes in another DN dataset (GSE96804), their up-stream regulators, including microRNAs and transcription factors were predicted and a regulatory network comprising of all these molecules was constructed. Results After normalization and analysis of the dataset, 2475 significant DEGs were identified and clustered into six different co-expression modules by WGCNA algorithm. Then, DEGs of each module were subjected to functional enrichment analyses and PPI network constructions. Metabolic processes, cell cycle control, and apoptosis were among the top enriched terms. In the next step, 23 hub genes were identified among the modules in genes and five of them, including FN1, SLC2A2, FABP1, EHHADH and PIPOX were validated in another DN dataset. In the regulatory network, FN1 was the most affected hub gene and mir-27a and REAL were recognized as two main upstream-regulators of the hub genes. Conclusions The identified hub genes from the hearts of co-expression modules could widen our understanding of the DN development and might be of targets of future investigations, exploring their therapeutic potentials for treatment of this complicated disease.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of diabetic nephropathy expression profile based on weighted gene co-expression network analysis algorithm

2021

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“…Elevation of plasma FFAs is regarded as a crucial pathogenic factor in the development and progression of DN [ 24 ]. To establish a model of PA-induced podocyte death, podocytes were cultured for 24 h in RPMI-1640 medium containing PA from 300 to 800 µM.…”

Section: Resultsmentioning

confidence: 99%

Fungus-Derived 3-Hydroxyterphenyllin and Candidusin A Ameliorate Palmitic Acid-Induced Human Podocyte Injury via Anti-Oxidative and Anti-Apoptotic Mechanisms

et al. 2022

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Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. An elevated fatty acid plasma concentration leads to podocyte injury and DN progression. This study aimed to identify and characterize cellular mechanisms of natural compounds that inhibit palmitic acid (PA)–induced human podocyte injury. By screening 355 natural compounds using a cell viability assay, 3-hydroxyterphenyllin (3-HT) and candidusin A (CDA), isolated from the marine-derived fungus Aspergillus candidus PSU-AMF169, were found to protect against PA-induced podocyte injury, with half-maximal inhibitory concentrations (IC50) of ~16 and ~18 µM, respectively. Flow cytometry revealed that 3-HT and CDA suppressed PA-induced podocyte apoptosis. Importantly, CDA significantly prevented PA-induced podocyte barrier impairment as determined by 70 kDa dextran flux. Reactive oxygen species (ROS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) direct scavenging assays indicated that both compounds exerted an anti-oxidative effect via direct free radical–scavenging activity. Moreover, 3-HT and CDA upregulated the anti-apoptotic Bcl2 protein. In conclusion, 3-HT and CDA represent fungus-derived bioactive compounds that have a novel protective effect on PA-induced human podocyte apoptosis via mechanisms involving free radical scavenging and Bcl2 upregulation.

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“…Lipotoxicity is defined as ectopic fat distribution in the peripheral organs with subsequent injurious effects in end organs, including the kidney, [ 172 , 173 , 174 , 175 ] and skeletal muscle [ 176 , 177 , 178 ]. In terms of cellular energy production, long-chain fatty acyl-CoA is esterified with carnitine in the cytoplasm, and then, the carnitine shuttle serves to carry it from the cytosol to the mitochondria, and thus, the carnitine nutritional supplement is expected to enhance or normalize long-chain fatty acid metabolism.…”

Section: Exploration Of Interventions To Overcome Uremic Sarcopenimentioning

confidence: 99%

Uremic Sarcopenia: Clinical Evidence and Basic Experimental Approach

et al. 2020

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Sustained physical activity extends healthy life years while a lower activity due to sarcopenia can reduce them. Sarcopenia is defined as a decrease in skeletal muscle mass and strength due not only to aging, but also from a variety of debilitating chronic illnesses such as cancer and heart failure. Patients with chronic kidney disease (CKD), who tend to be cachexic and in frail health, may develop uremic sarcopenia or uremic myopathy due to an imbalance between muscle protein synthesis and catabolism. Here, we review clinical evidence indicating reduced physical activity as renal function deteriorates and explore evidence-supported therapeutic options focusing on nutrition and physical training. In addition, although sarcopenia is a clinical concept and difficult to recapitulate in basic research, several in vivo approaches have been attempted, such as rodent subtotal nephrectomy representing both renal dysfunction and muscle weakness. This review highlights molecular mechanisms and promising interventions for uremic sarcopenia that were revealed through basic research. Extensive study is still needed to cast light on the many aspects of locomotive organ impairments in CKD and explore the ways that diet and exercise therapies can improve both outcomes and quality of life at every level.

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Podocyte lipotoxicity in diabetic kidney disease

Cited by 18 publications

References 9 publications

Comprehensive analysis of diabetic nephropathy expression profile based on weighted gene co-expression network analysis algorithm

Comprehensive analysis of diabetic nephropathy expression profile based on weighted gene co-expression network analysis algorithm

Fungus-Derived 3-Hydroxyterphenyllin and Candidusin A Ameliorate Palmitic Acid-Induced Human Podocyte Injury via Anti-Oxidative and Anti-Apoptotic Mechanisms

Uremic Sarcopenia: Clinical Evidence and Basic Experimental Approach

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