HIV compromises integrity of the podocyte actin cytoskeleton through downregulation of the vitamin D receptor

Chandel, Nirupama; Sharma, Bipin; Husain, Mohammad; Salhan, Divya; Singh, Tejinder; Rai, Partab; Mathieson, Peter W.; Saleem, Moin A.; Malhotra, Ashwani; Singhal, Pravin C.

doi:10.1152/ajprenal.00717.2012

Cited by 31 publications

(46 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These studies indicate that APOL1Vs may cause particularly severe renal injury in the setting of HIV infection. In a previous study, we noted that HIV increased lysosomal enzyme cathepsin L activity, which further compromised the integrity of the podocyte cytoskeleton (7). Taken together, we speculate that APOL1Vs and HIV may act synergistically on such lysosomal damage, leading to enhanced leakage of lysosomal components, exceeding the capacity to deal with damaged lysosomes by normally available pathways, and stronger cytosol cathepsin L activity than in the case of either APOL1Vs or HIV alone.…”

Section: Discussionmentioning

confidence: 58%

See 1 more Smart Citation

APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability

Lan

Jhaveri

Cheng

et al. 2014

American Journal of Physiology-Renal Physiology

Self Cite

156

210

View full text Add to dashboard Cite

Development of higher rates of nondiabetic glomerulosclerosis (GS) in African Americans has been attributed to two coding sequence variants (G1 and G2) in the APOL1 gene. To date, the cellular function and the role of APOL1 variants (Vs) in GS are still unknown. In this study, we examined the effects of overexpressing wild-type (G0) and kidney disease risk variants (G1 and G2) of APOL1 in human podocytes using a lentivirus expression system. Interestingly, G0 inflicted podocyte injury only at a higher concentration; however, G1 and G2 promoted moderate podocyte injury at lower and higher concentrations. APOL1Vs expressing podocytes displayed diffuse distribution of both Lucifer yellow dye and cathepsin L as manifestations of enhanced lysosomal membrane permeability (LMP). Chloroquine attenuated the APOL1Vs-induced increase in podocyte injury, consistent with targeting lysosomes. The chloride channel blocker DIDS prevented APOL1Vs- induced injury, indicating a role for chloride influx in osmotic swelling of lysosomes. Direct exposure of noninfected podocytes with conditioned media from G1- and G2-expressing podocytes also induced injury, suggesting a contributory role of the secreted component of G1 and G2 as well. Adverse host factors (AHFs) such as hydrogen peroxide, hypoxia, TNF-α, and puromycin aminonucleoside augmented APOL1- and APOL1Vs-induced podocyte injury, while the effect of human immunodeficiency virus (HIV) on podocyte injury was overwhelming under conditions of APOLVs expression. We conclude that G0 and G1 and G2 APOL1 variants have the potential to induce podocyte injury in a manner which is further augmented by AHFs, with HIV infection being especially prominent.

show abstract

Section: Discussionmentioning

confidence: 58%

“…Lysosomes were stained with Lucifer yellow (Invitrogen) and LysoTracker Red (Invitrogen) as described previously (6,7). Briefly, cells were cultured overnight in the medium containing 1 mg/ml Lucifer yellow, and then 500 nM LysoTracker was added followed by an additional 30-min incubation.…”

Section: Methodsmentioning

confidence: 99%

APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability

Lan

Jhaveri

Cheng

et al. 2014

American Journal of Physiology-Renal Physiology

Self Cite

156

210

View full text Add to dashboard Cite

show abstract

“…Similarly, HIV-induced down regulation of VDR expression was associated with ROS generation, lysosomal cathepsin-L leak and loss of integrity of podocyte actin cytoskeleton (16); whereas, restoration of VDR expression provided protection. These studies indicated that VDR expression is critical for the maintenance of kidney cell phenotype in HIV milieu.…”

mentioning

confidence: 99%

Epigenetic Modulation of Human Podocyte Vitamin D Receptor in HIV Milieu

Chandel

Ayasolla

Lan

et al. 2015

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

HIV has been reported to induce podocyte injury through down regulation of vitamin D receptor (VDR) and activation of renin angiotensin system (RAS); however, the involved mechanism is not clear. Since HIV has been reported to modulate gene expression via epigenetic phenomena, we asked whether epigenetic factors are contributing to down regulation of VDR. Kidney cells in HIV transgenic mice as well as HIV-infected podocytes (HIV/HPs) displayed enhanced expression of SNAIL, a repressor of VDR. To elucidate the mechanism, we studied the effect of HIV on expression of molecules involved in SNAIL repressor complex formation and demonstrated that HIV enhancesexpression of histone deacetylase (HDAC) 1, DNA methyl transferase (DNMT) 3b and DNMT1. 293T cells, when stably transfected with SNAIL (SNAIL/293T), displayed suppressed transcription and translation of VDR. In SNAIL/293T cells, co-immunoprecipitation studies revealed the association of HDAC1, DNMT3b, DNMT1, and mSin3A with SNAIL. Chromatin immunoprecipitation (ChIP) experiments confirmed the presence of the SNAIL repressor complex at the VDR promoter. Consistent with the enhanced DNA methyl transferase expression in HIV/HPs, there was an increased CpG methylation at the VDR promoter. ChIP assay confirmed occurrence of H3K4 trimethylation on SNAIL promoter. Neither VDR agonist (VDA) nor an HDAC inhibitor (HDACI) nor demethylating agent (DAC) individually could optimally upregulate VDR in HIV milieu. However, VDA and HDACI when combined were successful in de-repressing VDR expression. Our findings demonstrate that SNAIL recruits multiple chromatin enzymes to form a repressor complex in HIV milieu which down regulates VDR expression.

show abstract

“…This phenomenon may also be due to direct viral injury to the kidney, accelerated organ aging or individual dietary habits (19) . Direct viral infection of renal epithelial cells disturbs podocyte structure and function with subsequent upregulation of renin-angiotensin system which is held to central to the pathophysiology of hyperfiltration (20)(21)(22) .…”

Section: Discussionmentioning

confidence: 99%

Characteristics and Associations of Renal Dysfunction at Presentation in Haart-Naïve HIV-Infected Subjects in Port Harcourt, Nigeria

Richard¹,

O²

2016

jmscr

View full text Add to dashboard Cite

show abstract

HIV compromises integrity of the podocyte actin cytoskeleton through downregulation of the vitamin D receptor

Abstract: compromises integrity of the podocyte actin cytoskeleton through downregulation of the vitamin D receptor.

Cited by 31 publications

References 52 publications

APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability

APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability

Epigenetic Modulation of Human Podocyte Vitamin D Receptor in HIV Milieu

Characteristics and Associations of Renal Dysfunction at Presentation in Haart-Naïve HIV-Infected Subjects in Port Harcourt, Nigeria

Contact Info

Product

Resources

About