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DACH1 attenuated PA-induced renal tubular injury through TLR4/MyD88/NF-κB and TGF-β/Smad signalling pathway

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Abstract

Background

Palmitic acid (PA), the major saturated fatty acid in the blood, often induces the initiation and progression of diabetic kidney disease (DKD). However, the underlying mechanism remains unclear. DACH1 is an important regulator of kidney functions. Herein, we investigated the roles of DACH1 in PA-induced kidney injury.

Methods

Clinical data from the NHANES database were subjected to analyse the association between serum PA (sPA), blood glucose and kidney function. Molecular docking of PA was performed with DACH1. Immunohistochemistry, cell viability, annexin V/7-AAD double staining, TUNEL assay, immunofluorescent staining, autophagic flux analysis, qRT-PCR and western blot were performed.

Results

Clinical data confirmed that sPA was increased significantly in the pathoglycemia individuals compared with controls and correlated negatively with renal function. Our findings suggested that PA could dock with DACH1. DACH1 enhances cell viability by inhibiting apoptosis and attenuating autophagy blockage induced by PA. Furthermore, the results demonstrated that DACH1 ameliorated inflammation and fibrosis through TLR4/MyD88/NF-κB and TGF-β/Smad signalling pathway in PA-treated renal tubular epithelial cell line (HK-2).

Conclusions

This study proved that sPA presents a risk factor for kidney injuries and DACH1 might serve as a protective target against renal function deterioration in diabetic patients.

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Data availability

Data are available upon request to the corresponding author.

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Acknowledgements

Jie Lin and Bo Li contribute equally to this work and are co-first authors. Jie Zhou, Xiaomiao Li and Yinlan Bai are co-corresponding authors.

Funding

This work was supported by the National Natural Science Foundation of China (NO.82070839 to JZ) and 2017 China Diabetes Excellence Research Project to JZ.

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Author notes

  1. J. Lin and B. Li contribute equally to this work and are co-first authors.

Authors and Affiliations

  1. Department of Endocrinology, Xijing Hospital, Air Force Medical University, No.127 Changle West Road, Xi’an, 710032, China

    J. Lin, B. Li, Q. Xu, X. Wang, Y. Wang, X. M. Li & J. Zhou

  2. Department of Pharmacology, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medical of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Air Force Medical University, Xi’an, 710032, China

    Y. S. Liu

  3. Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, 710032, China

    Y. L. Kang & Y. L. Bai

  4. The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712099, China

    Y. Lei

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Contributions

JL and BL: experiments, statistics and discussion. QX, YSL, YW, YLK and XW: experiments and data analysis. YL, XML, YLB: data analysis and discussion. JZ: design, analysis, discussion and article revision. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Y. L. Bai, X. M. Li or J. Zhou.

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The authors declare there are no conflicts of competing interest.

Ethical approval

The NHANES protocol was approved by the institutional review board of the Centers for Disease Control and Prevention. As a matter of policy, our local Research Ethics Committee does not review secondary analyses of duly approved, publicly available data. All animal experiments were approved by the Animal Care and Use Committee at Air Force Medical University and were in accordance with the declaration of the National Institute of Health Guide for Care and Use of Laboratory Animals.

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Supplementary Information

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40618_2023_2253_MOESM1_ESM.tif

Supplementary file1 Fig. 1 The association between serum lipid level, blood glucose level, and eGFR. A, B Comparing with the control group, the median values of TG and TC in the DM, IFG, and IGT groups were significantly higher (all with P < 0.001). C, D Pearson correlation analysis indicated that levels of TG and TC were negatively associated with eGFR (all with P < 0.001). TG triglyceride, TC total cholesterol, IGT impaired glucose tolerance, IFG impaired fasting glucose, DM diabetes mellitus, eGFR estimated glomerular filtration rate. (TIF 8184 KB)

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Lin, J., Li, B., Xu, Q. et al. DACH1 attenuated PA-induced renal tubular injury through TLR4/MyD88/NF-κB and TGF-β/Smad signalling pathway. J Endocrinol Invest (2023). https://doi.org/10.1007/s40618-023-02253-7

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