APOL1 and kidney cell function

Kumar, Vinod; Singhal, Pravin C.

doi:10.1152/ajprenal.00233.2019

Cited by 22 publications

(23 citation statements)

References 106 publications

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“…There is an ongoing controversy regarding the role of cellular expression of APOL1 risk alleles in terms of gain or loss of function . As far as the present study is concerned, APOL1G1 and APOL1G2 contributed to the altered structural configuration of channels which is likely to contribute to K + efflux.…”

Section: Discussionmentioning

confidence: 73%

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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Section: Discussionmentioning

confidence: 73%

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

et al. 2019

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“…However, with high-grade proteinuria, retinoic acid is sequestered by albumin in the Bowman space 58 and parietal epithelial cell differentiation into podocytes is impaired. The absence of APOL1 also promotes parietal epithelial cell quiescence; the microRNA miR-193a suppresses APOL1 translation 59 . Under conditions of mechanical stress 60 , impaired APOL1-miR-193a axis (for example, in those with the G1 or G2 genotype) 59 or persistent NOTCH expression 61 , activated parietal epithelial cells cannot properly differentiate into podocytes and contribute to the formation of hyperplastic lesions and fibrous lesions, including FSGS 58,62 , by synthesizing and releasing extracellular matrix 63 (FiG.…”

Section: Oncotic Pressurementioning

confidence: 99%

Podocytopathies

Kopp

Anders

Suszták

et al. 2020

Nat Rev Dis Primers

298

270

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Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.

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“…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%

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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APOL1 and kidney cell function

Cited by 22 publications

References 106 publications

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

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

Podocytopathies

MiR193a Modulation and Podocyte Phenotype

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