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Modulation of APOL1-miR193a Axis Prevents Podocyte Dediffrentiation in High Glucose Milieu

Research output: Contribution to journalArticle

  • Abheepsa Mishra
  • Kamesh Ayasolla
  • Vinod Kumar
  • Xiqian Lan
  • Himanshu Vashistha
  • Rukhsana Aslam
  • Ali Hussain
  • Sheetal Chowdhary
  • Shadafarin Marashi Shoshtari
  • Nitpriya Paliwal
  • Waldemar Popik
  • Moin A Saleem
  • Ashwani Malhotra
  • Leonard G Meggs
  • Karl Skorecki
  • Pravin C Singhal
Original languageEnglish
Pages (from-to)832-843
Number of pages12
JournalAJP - Renal Physiology
Volume314
Issue number5
Early online date1 May 2018
DOIs
DateAccepted/In press - 8 Jan 2018
DateE-pub ahead of print - 1 May 2018
DatePublished (current) - May 2018

Abstract

The loss of podocyte (PD) molecular phenotype is an important feature of diabetic podocytopathy. We hypothesized that high glucose (HG) induces dedifferentiation in differentiated podocytes (DPD) through alterations in APOL1-microRNA (miR) 193a axis. HG-induced DPDs dedifferentiation manifested in the form of down regulation of WT1 and upregulation of PAX2 expression. WT1- silenced DPDs displayed enhanced expression of PAX2. Immunoprecipitation (IP) of DPD cellular lysates with anti-WT1 antibody revealed formation of WT1 repressor complexes containing Polycomb group proteins (PcG), EZH2, Menin, and DNA methyl transferase (DNMT1), whereas, silencing of either WT1 or DNMT1 disrupted this complex with enhanced expression of PAX2. HG-induced DPDs dedifferentiation was associated with a higher expression of miR193a, whereas, inhibition of miR193a prevented DPDs dedifferentiation in HG milieu. HG down regulated DPDs expression of APOL1. MiR193a-overexpressing DPDs displayed down regulation of APOL1 and enhanced expression of dedifferentiating markers; conversely, silencing of miR193a enhanced the expression of APOL1 and also preserved DPDs phenotype. Moreover, stably APOL1G0-overexpressing DPDs displayed the enhanced expression of WT1 but attenuated expression of miR193a; nonetheless, silencing of APOL1 reversed these effects. Since silencing of APOL1 enhanced miR193a expression as well as dedifferentiation in DPDs, it appears that down regulation of APOL1 contributed to dedifferentiation of DPDs through enhanced miR193a expression in HG milieu. Vitamin D receptor agonist (VDA) down regulated miR193a, upregulated APOL1 expression, and prevented dedifferentiation of DPDs in HG milieu. These findings suggest that modulation of the APOL1-miR193a axis carries a potential to preserve DPDs molecular phenotype in HG milieu.

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    Rights statement: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via the American Physiological Society at https://doi.org/10.1152/ajprenal.00541.2017 . Please refer to any applicable terms of use of the publisher.

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