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Kruppel-like factor 4 improves obesity-related nephropathy through increasing mitochondrial biogenesis and activities.

ABSTRACT: Obesity is positively linked to multiple metabolic complications including renal diseases. Several studies have demonstrated Kruppel-like factor 4 (KLF4) participated in renal dysfunction and structural disorders in acute kidney injuries, but whether it affected the process of chronic kidney diseases was unknown. Therefore, present study was to disclose the role of renal KLF4 in dietary-induced renal injuries and underlying mechanisms in obesity. Through utilizing high-fat diet-fed mice and human renal biopsies, we provided the physiological roles of KLF4 in protecting against obesity-related nephropathy. Decreased levels of renal KLF4 were positively correlated with dietary-induced renal dysfunction, including increased levels of creatinine and blood urea nitrogen. Overexpression of renal KLF4 suppressed inflammatory response in palmitic acid-treated mouse endothelial cells. Furthermore, overexpressed KLF4 also attenuated dietary-induced renal functional disorders, abnormal structural remodelling and inflammation. Mechanistically, KLF4 maintained renal mitochondrial biogenesis and activities to combat obesity-induced mitochondrial dysfunction. In clinical renal biopsies and plasma, the renal Klf4 level was negatively associated with circulating levels of creatinine but positively associated with renal creatinine clearance. In conclusions, the present findings firstly supported that renal KLF4 played an important role in combating obesity-related nephropathy, and KLF4/mitochondrial function partially determined the energy homeostasis in chronic kidney diseases.

SUBMITTER: Jin L

PROVIDER: S-EPMC6991690 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Kruppel-like factor 4 improves obesity-related nephropathy through increasing mitochondrial biogenesis and activities.

Jin Lingwei L Ye Hanyang H Pan Min M Chen Yan Y Ye Bairu B Zheng Yu Y Huang Wenwen W Pan Shufang S Shi Zhen Z Zhang Jing J

Journal of cellular and molecular medicine 20191204 2

Obesity is positively linked to multiple metabolic complications including renal diseases. Several studies have demonstrated Kruppel-like factor 4 (KLF4) participated in renal dysfunction and structural disorders in acute kidney injuries, but whether it affected the process of chronic kidney diseases was unknown. Therefore, present study was to disclose the role of renal KLF4 in dietary-induced renal injuries and underlying mechanisms in obesity. Through utilizing high-fat diet-fed mice and huma ...[more]

PMID: 31800161

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Project description:BackgroundRibosomal biogenesis and ribosomal proteins have attracted attention in the context of tumor biology in recent years. Instead of being mere translational machineries, ribosomes might play an active role in tumor initiation and progression. Despite its importance, regulation of ribosomal biogenesis is still not completely understood.MethodsUsing Gene Set Enrichment Analysis of RNA sequencing and proteomical mass spectrometry data in breast cancer cells expressing Krüppel-like factor 7 (KLF7), we identified processes altered by this transcription factor. In silico analyses of a cohort of breast cancer patients in The Cancer Genome Atlas confirmed our finding. We further verified the role of KLF7 the identified ribosomal processes in in vitro assays of mammary carcinoma cell lines and analyses of breast cancer patients' tissue slices.ResultsWe identified the transcription factor Krüppel-like factor 7 (KLF7) as a regulator of ribosomal biogenesis and translation in breast cancer cells and tissue. Highly significant overlapping processes related to ribosomal biogenesis were identified in proteomics and transcriptomics data and confirmed in patients' breast cancer RNA Seq data. Further, nucleoli, the sites of ribosomal biogenesis, were morphologically altered and quantitatively increased in KLF7-expressing cells. Pre-rRNA processing was identified as one potential process affected by KLF7. In addition, an increase in global translation independent from proliferation and transcription was observed upon exogenous KLF7 expression in vitro. Importantly, in a cohort of breast cancer patients, KLF7-expression levels correlated with aggressiveness of the intrinsic breast cancer subtype and tumor grading. Moreover, KLF7 correlated with nucleolar characteristics in human breast tumor tissue, indicating a role for KLF7 in ribosomal biogenesis.ConclusionIn mammary carcinoma, KLF7 is involved in ribosomal biogenesis. Alterations of ribosomal biogenesis has far reaching quantitative and qualitative implications for the proteome of the cancer cells. This might influence the aggressiveness of cancer cells.

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Kruppel-like factor 4 improves obesity-related nephropathy through increasing mitochondrial biogenesis and activities.

Publications

Kruppel-like factor 4 improves obesity-related nephropathy through increasing mitochondrial biogenesis and activities.

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