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

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.

• Authors: Piyush Gondaliya, Aishwarya P Dasare, Kavya Jash, Rakesh Kumar Tekade, Akshay Srivastava, Kiran Kalia
• Journal: Journal of diabetes and metabolic disorders (J Diabetes Metab Disord) Vol. 19 Issue 1 Pg. 13-27 (Jun 2020) ISSN: 2251-6581 [Print] Switzerland
• PMID: 32550152 (Publication Type: Journal Article)
• Copyright: © Springer Nature Switzerland AG 2019.