Disruption of APOL1-miR193a Axis Induces Disorganization of Podocyte Actin Cytoskeleton

Kumar, Vinod; Paliwal, Nitpriya; Ayasolla, Kamesh; Vashistha, Himanshu; Jha, Alok; Chandel, Nirupama; Chowdhary, Sheetal; Saleem, Moin A.; Malhotra, Ashwani; Chander, Praveen N.; Skorecki, Karl; Singhal, Pravin C.

doi:10.1038/s41598-019-39376-y

Cited by 22 publications

(38 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, APOL1 may interact with GTPase or SNARE proteins, thus interfering with autophagy maturation and lysosome fusion ( 52 ). APOL1 renal risk alleles (G1 and G2), also called renal risk variants (RRVs), inhibit the APOL1-miR193a axis of differentiated podocytes (DPDs) ( 53 ), resulting in a decrease in the assembly of PI3KC3-ATG14L and PI3KC3-anti-UV radiation resistance associated gene complexes needed for autophagy nucleus formation and maturation. This is a separate pathway by which APOL1 can trigger lysosome-mediated autophagy ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

The clinical significance of apolipoprotein L1 in head and neck squamous cell carcinoma

Zhong¹,

Chen

et al. 2020

Oncol Lett

View full text Add to dashboard Cite

Approximately 500,000 new head and neck squamous cell carcinoma (HNSCC) cases are detected every year around the world, and its incidence ranks sixth among all cancer types globally. Among these cases, oral squamous cell carcinoma (OSCC) and laryngeal squamous cell carcinoma (LSCC) are HNSCC subtypes with high incidence rates, especially in China. The present study examines the association between the apolipoprotein L1 (APOL1) mRNA and protein expression and clinical parameters in HNSCC. The two most common types (oral and larynx) of HNSCC were selected for subgroup analyses. Immunohistochemistry (IHC) was used to detect APOL1 protein expression levels in HNSCC clinical specimens. It was demonstrated that APOL1 protein expression in 221 cases of HNSCC was higher compared with that in normal tissues. Consistent upregulation of APOL1 protein was also found in subgroups of OSCC and LSCC. Through mining the ArrayExpress, The Cancer Genome Atlas and the Gene Expression Omnibus databases, microarrays and RNA sequencing data for HNSCC were retrieved, which were used to analyze APOL1 mRNA expression levels. The results showed that APOL1 expression was higher in both OSCC and LSCC subtypes, as well as in HNSCC, compared with that in non-cancerous squamous epithelium. The summary receiver operating characteristic analysis showed that APOL1 had potential as a diagnostic biomarker for HNSCC, OSCC and LSCC. Thus, upregulation of APOL1 may contribute to the tumorigenesis of HNSCC.

show abstract

Section: Discussionmentioning

confidence: 99%

The clinical significance of apolipoprotein L1 in head and neck squamous cell carcinoma

Zhong¹,

Chen

et al. 2020

Oncol Lett

View full text Add to dashboard Cite

show abstract

“…Western blot studies were carried out as described previously . Briefly, control and experimental cells were harvested, lysed in RIPA buffer containing 50 m m Tris/Cl (pH 7.5), 150 m m NaCl, 1mM EDTA, 1% NP‐40, 0.25% deoxycholate, 0.1% SDS, 1× protease inhibitor cocktail (Calbiochem, San Diego, CA, USA; Cocktail Set I), 1 m m PMSF, and 0.2 m m sodium orthovanadate.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

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/

show abstract

“…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%

“…Western blot studies were carried out as described previously [10][11][12]. Briefly, control and experimental cells were harvested, lysed in RIPA buffer containing 50 mM Tris-Cl (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1% NP-40, 0.25% Deoxycholate, 0.1% SDS, 1X protease inhibitor cocktail (Calbiochem, Sigma Aldrich, St. Louis, MO, USA Cocktail Set I), 1 mM Phenylmethylsulfonyl fluoride (PMSF), and 0.2 mM sodium orthovanadate.…”

Section: Western Blot Studiesmentioning

confidence: 99%

See 1 more Smart Citation

MiR193a Modulation and Podocyte Phenotype

Jha

Saha

Ayasolla

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Disruption of APOL1-miR193a Axis Induces Disorganization of Podocyte Actin Cytoskeleton

Cited by 22 publications

References 49 publications

The clinical significance of apolipoprotein L1 in head and neck squamous cell carcinoma

The clinical significance of apolipoprotein L1 in head and neck squamous cell carcinoma

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

MiR193a Modulation and Podocyte Phenotype

Contact Info

Product

Resources

About