Role of Apolipoprotein L1 in Human Parietal Epithelial Cell Transition

Kumar, Vinod; Vashistha, Himanshu; Lan, Xiqian; Chandel, Nirupama; Ayasolla, Kamesh; Shoshtari, Seyedeh Shadafarin Marashi; Aslam, Rukhsana; Paliwal, Nitpriya; Abbruscato, Frank; Mikulak, Joanna; Popik, Waldemar; Atta, Mohamed G.; Chander, Praveen N.; Malhotra, Ashwani; Meyer-Schwesinger, Catherine; Skorecki, Karl; Singhal, Pravin C.

doi:10.1016/j.ajpath.2018.07.025

Cited by 30 publications

(40 citation statements)

References 38 publications

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“…VDA down-regulated miR193a both undifferentiated as well as differentiated podocytes. In reported studies, VDA treatment not only induced APOL1 in parietal epithelial cells but promoted the transition of parietal epithelial cells to podocytes [7]. The present study further confirms that modulation of miR193a can be used as a strategy to maintain the podocyte molecular phenotype.…”

Section: Discussionsupporting

confidence: 86%

“…Down-regulation of miR193a has been reported in cells with enhanced expression of APOL1; the latter is also considered a marker of podocyte maturation [7,10,11,13]. On that account, VDA-induced down-regulation of miR193a could be used to sustain the podocyte molecular phenotype.…”

Section: Discussionmentioning

confidence: 98%

“…SC400232; OriGene, Rockville, MD, USA), and empty vector (25 nM; pCMV-MIR; OriGene, Rockville, MD, USA) were transfected in the control and experimental cells (UPDs or DPDs) using Lipofectamine 3000 Transfection Reagent (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer's protocol. Details are described in our recent publications [7,10,11].…”

Section: Transfection Of a Specific Mir193a Inhibitor And Mir193a Expmentioning

confidence: 99%

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MiR193a Modulation and Podocyte Phenotype

Jha

Saha

Ayasolla

et al. 2020

Cells

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Apolipoprotein L1 (APOL1)-miR193a axis has been reported to play a role in the maintenance of podocyte homeostasis. In the present study, we analyzed transcription factors relevant to miR193a in human podocytes and their effects on podocytes’ molecular phenotype. The motif scan of the miR193a gene provided information about transcription factors, including YY1, WT1, Sox2, and VDR-RXR heterodimer, which could potentially bind to the miR193a promoter region to regulate miR193a expression. All structure models of these transcription factors and the tertiary structures of the miR193a promoter region were generated and refined using computational tools. The DNA-protein complexes of the miR193a promoter region and transcription factors were created using a docking approach. To determine the modulatory role of miR193a on APOL1 mRNA, the structural components of APOL1 3’ UTR and miR193a-5p were studied. Molecular Dynamic (MD) simulations validated interactions between miR193a and YY1/WT1/Sox2/VDR/APOL1 3′ UTR region. Undifferentiated podocytes (UPDs) displayed enhanced miR193a, YY1, and Sox2 but attenuated WT1, VDR, and APOL1 expressions, whereas differentiated podocytes (DPDs) exhibited attenuated miR193a, YY1, and Sox2 but increased WT1, VDR, APOL1 expressions. Inhibition of miR193a in UPDs enhanced the expression of APOL1 as well as of podocyte molecular markers; on the other hand, DPD-transfected with miR193a plasmid showed downing of APOL1 as well as podocyte molecular markers suggesting a causal relationship between miR193a and podocyte molecular markers. Silencing of YY1 and Sox2 in UPDs decreased the expression of miR193a but increased the expression of VDR, and CD2AP (a marker of DPDs); in contrast, silencing of WT1 and VDR in DPDs enhanced the expression of miR193a, YY1, and Sox2. Since miR193a-downing by Vitamin D receptor (VDR) agonist not only enhanced the mRNA expression of APOL1 but also of podocyte differentiating markers, suggest that down-regulation of miR193a could be used to enhance the expression of podocyte differentiating markers as a therapeutic strategy.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 98%

Section: Transfection Of a Specific Mir193a Inhibitor And Mir193a Expmentioning

confidence: 99%

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MiR193a Modulation and Podocyte Phenotype

Jha

Saha

Ayasolla

et al. 2020

Cells

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“…One may argue that lower expression of APOL1 risk alleles could be potentially toxic in vivo , and one need not compare them with the expression levels of APOL1 in vitro studies. This notion is further supported by the enhanced expression of APOL1 variants by PD in HIV‐associated nephropathy patients .…”

Section: Discussionmentioning

confidence: 74%

Alterations in plasma membrane ion channel structures stimulate NLRP3 inflammasome activation in APOL1 risk milieu

et al. 2019

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We evaluated alterations in the structural configurations of channels and activation of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome formation in apolipoprotein L1 (APOL1) risk and nonrisk milieus. APOL1G1-and APOL1G2-expressing podocytes (PD) displayed enhanced K + efflux, induction of pyroptosis, and escalated transcription of interleukin (IL)-1b and IL-18. APOL1G1-and APOL1G2-expressing PD promoted the transcription as well as translation of proteins involved in the formation of inflammasomes. Since glyburide (a specific inhibitor of K + efflux channels) inhibited the transcription of NLRP3, IL-1b, and IL-18, the role of K + efflux in the activation of inflammasomes in APOL1 risk milieu was implicated. To evaluate the role of structural alterations in K + channels in plasma membranes, bioinformatics studies, including molecular dynamic simulation, were carried out. Superimposition of bioinformatics reconstructions of APOL1G0, G1, and G2 showed several aligned regions. The analysis of pore-lining residues revealed that Ser342 and Tyr389 are involved in APOL1G0 pore formation and the altered conformations resulting from the Ser342Gly and Ile384Met mutation in the case of APOLG1 and deletion of the Tyr389 residue in the case of APOL1G2 are expected to alter pore characteristics, including K + ion selectivity. Analysis of multiple membrane (lipid bilayer) models of interaction with the peripheral protein, integral membrane protein, and multimer protein revealed that for an APOL1 multimer model, APOL1G0 is not energetically favorable while the APOL1G1 and APOL1G2 moieties favor the insertion of multiple ion channels into the lipid bilayer. We conclude that altered pore configurations carry the potential to facilitate K + ion transport in APOL1 risk milieu.Abbreviations AA, amino acid; APOL1, apolipoprotein L1; APOL1G0, APOL1 nonrisk allele; APOL1G1 and G2, APOL1 risk alleles/

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“…Interestingly, the recent recognition of the APOL1-miR-193a axis (AMA) has provided some insight into the purpose of APOL1's evolution in humans as an effort to enhance the podocyte renewal reservoir to support the increased longevity of humans. As a part of the AMA, APOL1 facilitates the maintenance of the podocyte molecular phenotype and their renewal in adverse milieus (53,55).…”

Section: Introductionmentioning

confidence: 99%

APOL1 and kidney cell function

Kumar

Singhal

2019

American Journal of Physiology-Renal Physiology

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The apolipoprotein L1 (APOL1) gene is unique to humans and gorillas and appeared ~33 million years ago. Since the majority of the mammals do not carry APOL1, it seems to be dispensable for kidney function. APOL1 renal risk variants (RRVs; G1 and G2) are associated with the development as well as progression of chronic kidney diseases (CKDs) at higher rates in populations with African ancestry. Cellular expression of two APOL1 RRVs has been demonstrated to induce cytotoxicity, including necrosis, apoptosis, and pyroptosis, in several cell types including podocytes; mechanistically, these toxicities were attributed to lysosomal swelling, K+ depletion, mitochondrial dysfunction, autophagy blockade, protein kinase receptor activation, ubiquitin D degradation, and endoplasmic reticulum stress; notably, these effects were found to be dose dependent and occurred only in overtly APOL1 RRV-expressing cells. However, cellular protein expressions as well as circulating blood levels of APOL1 RRVs were not elevated in patients suffering from APOL1 RRV-associated CKDs. Therefore, the question arises as to whether it is gain or loss of function on the part of APOL1 RRVs contributing to kidney cell injury. The question seems to be more pertinent after the recognition of the role of APOL1 nonrisk (G0) in the transition of parietal epithelial cells and preservation of the podocyte molecular phenotype through modulation of the APOL1-miR-193a axis. With this background, the present review analyzed the available literature in terms of the known function of APOL1 nonrisk and how the loss of these functions could have contributed to two APOL1 RRV-associated CKDs.

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Role of Apolipoprotein L1 in Human Parietal Epithelial Cell Transition

Cited by 30 publications

References 38 publications

MiR193a Modulation and Podocyte Phenotype

MiR193a Modulation and Podocyte Phenotype

Alterations in plasma membrane ion channel structures stimulate NLRP3 inflammasome activation in APOL1 risk milieu

APOL1 and kidney cell function

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