Krüppel-like factor 6–mediated loss of BCAA catabolism contributes to kidney injury in mice and humans

Proceedings of the National Academy of Sciences · 2021 · 68 citations

• Internal medicine
• Endocrinology
• Chemistry

and both kidney function and BCAA expression. Thus, targeting KLF6-mediated suppression of BCAA catabolism may serve as a key therapeutic target in AKI and kidney fibrosis.

Identification of key transcriptome biomarkers based on a vital gene module associated with pathological changes in Alzheimer’s disease

Aging · 2021 · 26 citations

• Biology
• Computational biology
• Bioinformatics

Dysregulation of transcriptome expression has been reported to play an increasingly significant role in AD. In this study, we firstly identified a vital gene module associated with the accumulation of β-amyloid (Aβ) and phosphorylated tau (p-tau) using the WGCNA method. The vital module, named target module, was then employed for the identification of key transcriptome biomarkers. For coding RNA, GNA13 and GJA1 were identified as key biomarkers based on ROC analysis. As for non-coding RNA, MEG3, miR-106a-3p, and miR-24-3p were determined as key biomarkers based on analysis of a ceRNA network and ROC analysis. Experimental analyses firstly confirmed that GNA13, GJA1, and ROCK2, a downstream effector of GNA13, were all increased in 5XFAD mice, compared to littermate mice. Moreover, their expression was increased with aging in 5XFAD mice, as Aβ and p-tau pathology developed. Besides, the expression of key ncRNA biomarkers was verified to be decreased in 5XFAD mice. GSEA results indicated that GNA13 and GJA1 were respectively involved in ribosome and spliceosome dysfunction. MEG3, miR-106a-3p, and miR-24-3p were identified to be involved in MAPK pathway and PI3K-Akt pathway based on enrichment analysis. In summary, we identified several key transcriptome biomarkers, which promoted the prediction and diagnosis of AD.

Podocyte-specific KLF4 is required to maintain parietal epithelial cell quiescence in the kidney

Science Advances · 2021 · 34 citations

• Cell biology
• Biology
• Neuroscience

Podocyte loss triggering aberrant activation and proliferation of parietal epithelial cells (PECs) is a central pathogenic event in proliferative glomerulopathies. Podocyte-specific Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor, is essential for maintaining podocyte homeostasis and PEC quiescence. Using mice with podocyte-specific knockdown of Klf4, we conducted glomerular RNA-sequencing, tandem mass spectrometry, and single-nucleus RNA-sequencing to identify cell-specific transcriptional changes that trigger PEC activation due to podocyte loss. Integration with in silico chromatin immunoprecipitation identified key ligand-receptor interactions, such as fibronectin 1 (FN1)–αVβ6, between podocytes and PECs dependent on KLF4 and downstream signal transducer and activator of transcription 3 (STAT3) signaling. Knockdown of Itgb6 in PECs attenuated PEC activation. Additionally, podocyte-specific induction of human KLF4 or pharmacological inhibition of downstream STAT3 activation reduced FN1 and integrin β 6 (ITGB6) expression and mitigated podocyte loss and PEC activation in mice. Targeting podocyte-PEC crosstalk might be a critical therapeutic strategy in proliferative glomerulopathies.

Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation

Kidney International · 2021 · 88 citations

• Biology
• Endocrinology
• Internal medicine