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miR-29b attenuates histone deacetylase-4 mediated podocyte dysfunction and renal fibrosis in diabetic nephropathy

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Abstract

Purpose

As epigenetic modifications like chromatin histone modifications have been suggested to play a role in the pathophysiology of Diabetic Nephropathy (DN) and are also found to be regulated by microRNAs. Our main purpose was to explore the role of microRNA in histone modulations associated with DN. There is downregulation of miR-29b due to advanced glycation end products in diabetes. Histone Deacetylase-4 (HDAC4) is amongst the histone modulators which promotes podocytes’ impairment and upregulates transforming growth factor-1 (TGF-β1) leading to renal fibrosis. Moreover, macrophage infiltration causes podocytes’ apoptosis and IL-6 mediated inflammation. As miR-29b is downregulated in diabetes and HDAC4, TGF-β1 and IL-6 could be the possible therapeutic targets in DN, our study was focussed on unveiling the role of miR-29b in modulation of HDAC4 and hence, in podocyte dysfunction and renal fibrosis in DN.

Methods

In silico analysis and luciferase assay were done to study the interaction between miR-29b and HDAC4. In-vitro DN model was developed in podocytes and miR-29b mimics were transfected. Also, podocytes were co-cultured with macrophage and miR-29b mimics were transfected. At the end, in-vivo DN model was generated in C57BL/6 J male mice and the effect of miR-29b mimics was reconfirmed.

Results

It was found that miR-29b targets the 3′ untranslated region of HDAC4. In both in-vitro and in-vivo DN model, downregulation of miR-29b and subsequent increase in HDAC4 expression was observed. The miR-29b mimics suppressed podocytes’ inflammation mediated through macrophages and attenuated HDAC4 expression, glomerular damage and renal fibrosis.

Conclusion

This study concludes that miR-29b regulates the expression of HDAC4 which plays a role in controlling renal fibrosis and podocytes’ impairment in DN.

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Acknowledgments

The research was carried out at National Institute of Pharmaceutical Education and Research- Ahmedabad with the financial support from the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India.

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Author notes

  1. Piyush Gondaliya and Aishwarya Dasare contributed equally and can be interchangeably written as first authors.

Authors and Affiliations

  1. Department of Biotechnology, National Institute of Pharmaceutical Education and Research- Ahmedabad, opposite Air force station, Palaj, Gandhinagar, Gujarat, 382355, India

    Piyush Gondaliya, Aishwarya P. Dasare, Kavya Jash & Kiran Kalia

  2. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad, opposite Air force station, Palaj, Gandhinagar, Gujarat, 382355, India

    Rakesh Kumar Tekade

  3. Department of Medical Devices, National Institute of Pharmaceutical Education and Research- Ahmedabad, opposite Air force station, Palaj, Gandhinagar, Gujarat, 382355, India

    Akshay Srivastava

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  1. Piyush Gondaliya
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Correspondence to Rakesh Kumar Tekade, Akshay Srivastava or Kiran Kalia.

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Animals studies

All applicable institutional guidelines for the care and use of animals were followed. All procedures performed in this study involving animals were in accordance with the ethical standards of the institution at which the study was conducted (NIPER-A institutional animal ethics committee, NIPER-A/IAEC/2017/032).

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Gondaliya, P., P. Dasare, A., Jash, K. et al. miR-29b attenuates histone deacetylase-4 mediated podocyte dysfunction and renal fibrosis in diabetic nephropathy. J Diabetes Metab Disord 19, 13–27 (2020). https://doi.org/10.1007/s40200-019-00469-0

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  • DOI: https://doi.org/10.1007/s40200-019-00469-0

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