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Disease Models & Mechanisms Dec 2019Notch pathway activation plays a central role in the pathogenesis of many glomerular diseases. We have previously shown that Notch4 expression was upregulated in various...
Notch pathway activation plays a central role in the pathogenesis of many glomerular diseases. We have previously shown that Notch4 expression was upregulated in various renal cells in human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) patients and rodent models of HIVAN. In this study, we examined whether the Notch pathway can be distinctly activated by HIV-1 gene products and whether Notch4, in particular, can influence disease progression. Using luciferase reporter assays, we did not observe activation of the promoter with the HIV protein Nef in podocytes. Further, we observed upregulated expression of a gamma secretase complex protein, presenilin 1, but not Notch4, in podocytes infected with an HIV-1 expression construct. To assess the effects of Notch4 on HIVAN disease progression, we engineered Tg26 mice with global deletion of the Notch4 intracellular domain ( ), which is required for signaling function. These mice ( ) showed a significant improvement in renal function and a significant decrease in mortality compared to Tg26 mice. Histological examination of kidneys showed that mice had overall glomerular, tubulointerstitial injury and a marked decrease in interstitial inflammation. A significant decrease in the proliferating cells was observed in the tubulointerstitial compartments of mice. Consistent with the diminished inflammation, kidneys from mice also showed a significant decrease in expression of the inflammatory cytokine transcripts and , as well as the master inflammatory transcription factor NF-κB ( transcripts and p65 protein). These data identify Notch4 as an important mediator of tubulointerstitial injury and inflammation in HIVAN and a potential therapeutic target.
Topics: AIDS-Associated Nephropathy; Animals; Cell Proliferation; Crosses, Genetic; Disease Models, Animal; Disease Progression; Female; Gene Deletion; HEK293 Cells; Humans; Inflammation; Kidney; Male; Mice; Mice, Transgenic; NF-kappa B p50 Subunit; Podocytes; Receptor, Notch4; Signal Transduction; Transcription Factor RelA; Treatment Outcome; nef Gene Products, Human Immunodeficiency Virus
PubMed: 31727625
DOI: 10.1242/dmm.040642 -
HIV Medicine Nov 2015Both renal disease and systemic inflammation predict non-AIDS-defining events and overall mortality in HIV-infected patients. Here, we sought to determine the...
OBJECTIVES
Both renal disease and systemic inflammation predict non-AIDS-defining events and overall mortality in HIV-infected patients. Here, we sought to determine the relationships between renal disease and circulating inflammation markers.
METHODS
We performed a secondary analysis of AIDS Clinical Trials Group Study A5224s to determine if markers of renal disease [urine protein:creatinine ratio (uPCR), urine albumin:creatinine ratio (uACR), and estimated glomerular filtration rate (eGFR), using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine and cystatin C-creatinine] were associated with markers of systemic inflammation [high-sensitivity C-reactive protein, interleukin-6, tumour necrosis factor (TNF)-α, soluble TNF-α receptor I (sTNFRI), sTNFRII, and soluble vascular cellular and intercellular adhesion molecules]. We correlated these renal and inflammatory markers prior to antiretroviral initiation and after 96 weeks of therapy.
RESULTS
We found that eGFR (estimated using CKD-EPI cystatin C-creatinine), uPCR, and uACR were significantly correlated with most assessed markers of systemic inflammation prior to antiretroviral initiation. uPCR and eGFR (using CKD-EPI cystatin C-creatinine), but not uACR, remained significantly correlated with most of the assessed inflammatory markers after 96 weeks of antiretroviral therapy (ART). Most of these correlations, although statistically significant, were < 0.50. eGFR using CKD-EPI creatinine was much less frequently associated with inflammation markers and only significantly correlated with sTNFR1 at week 0 and with sTNFRI and II at week 96.
CONCLUSIONS
Renal disease and function were associated with systemic inflammation in HIV infection, both before and after ART. Systemic inflammation may partially explain the relationships between proteinuria, albuminuria, and reduced renal function and future adverse outcomes.
Topics: Adult; Biomarkers; Female; Glomerular Filtration Rate; HIV Infections; Humans; Inflammation; Inflammation Mediators; Kidney Diseases; Male; Middle Aged; Molecular Sequence Data; Young Adult
PubMed: 25990642
DOI: 10.1111/hiv.12268 -
Journal of Infection in Developing... Sep 2020End-stage renal disease (ESRD) related to HIV is becoming a leading cause of renal replacement therapy requirement is some areas of the world. Our study aims to describe...
INTRODUCTION
End-stage renal disease (ESRD) related to HIV is becoming a leading cause of renal replacement therapy requirement is some areas of the world. Our study aims to describe the incidence and renal outcomes of HIV-associated nephropathy (HIVAN), and immune-mediated kidney disease related to HIV (HIVICK) in Colombia.
METHODOLOGY
A retrospective cohort study was performed, including all HIVAN or HIVICK incident cases assessed by the infectious diseases division in a high complexity institution in Colombia, between 2004 and 2018. A longitudinal data model under the Generalized Estimating Equations (GEE) method was used to determine changes on the glomerular filtration rate (GFR) over time.
RESULTS
Within a cohort composed by 1509 HIV-infected patients, we identified 22 with HIV-associated glomerular disease. Cumulative incidence was 1.45%. At diagnosis, GFR was above 30 mL/min in 90.8% of patients, and 77.2% displayed sub-nephrotic proteinuria. Factors associated with GFR at diagnosis were: level of CD4 (Coefficient 0.113, CI 95 %: 0.046, 0.179, p < 0.01), and the inverse of the CD4/CD8 ratio. The GEE model did not demonstrate significant changes in the GFR over a 3-year period. Findings were similar when comparing GFR at diagnosis with GFR at 12 (-3.9 mL/min/1.73m2, CI 95% -7.3, 0.4, p = 0.98), 24 (-2.47 mL/min/1.73m2, CI 95% -7.0, 2.1, p=0.85), and 36 months (0.39 mL/min/1.73m2, CI 95% -4.4, 5.2, p = 0.43) of follow-up.
CONCLUSIONS
Patients with glomerular disease associated with HIV have stable GFR over a 3-year period, and low rates of progression towards dialysis requirement. Differences with previous reports could be related with early diagnosis and treatment with highly active antiretroviral therapy.
Topics: AIDS-Associated Nephropathy; Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-CD8 Ratio; Colombia; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; HIV Infections; HIV-1; Humans; Kidney Failure, Chronic; Longitudinal Studies; Male; Middle Aged; Retrospective Studies
PubMed: 33031092
DOI: 10.3855/jidc.12030 -
Scientific Reports Nov 2019HIV-associated nephropathy (HIVAN) is a rapidly progressive kidney disease that is caused by HIV infection of renal epithelial cells with subsequent expression of viral...
HIV-associated nephropathy (HIVAN) is a rapidly progressive kidney disease that is caused by HIV infection of renal epithelial cells with subsequent expression of viral genes, including vpr. Antiretroviral therapy ameliorates HIVAN without eradicating HIV from the kidneys and the mechanism by which it protects kidneys is poorly understood. Since HIV protease inhibitors have "off target" cellular effects, we studied whether darunavir, the most commonly prescribed protease inhibitor, protects kidneys from HIV-induced injury via mechanisms independent of HIV protease and viral replication. Renal epithelial cells were transduced with lentiviruses encoding HIV (lacking protease and reverse transcriptase), Vpr, or vector control. Darunavir attenuated HIV and Vpr-induced activation of Stat3, Src, Erk, and cytokines, which are critical for HIVAN pathogenesis. We then studied HIV-transgenic mice, which develop HIVAN in the absence of HIV protease or reverse transcriptase. Mice were treated with darunavir, zidovudine, darunavir + zidovudine, or control. Darunavir and darunavir + zidovudine reduced albuminuria and histologic kidney injury and normalized expression of dysregulated proteins. RNA-seq analyses demonstrated that darunavir suppressed HIV-induced upregulation of immune response genes in human kidney cells. These data demonstrate that darunavir protects against HIV-induced renal injury via mechanisms that are independent of inhibition of HIV protease.
Topics: AIDS-Associated Nephropathy; Animals; Cell Line; Darunavir; HIV Protease Inhibitors; HIV-1; Humans; Kidney; MAP Kinase Signaling System; Mice; Mice, Transgenic; Zidovudine
PubMed: 31676833
DOI: 10.1038/s41598-019-52278-3 -
Experimental and Molecular Pathology Aug 2015Collapsing glomerulopathy and microcysts are characteristic histological features of HIV-associated nephropathy (HIVAN). We have previously reported the role of...
Collapsing glomerulopathy and microcysts are characteristic histological features of HIV-associated nephropathy (HIVAN). We have previously reported the role of epithelial mesenchymal transition (EMT) in the development of glomerular and tubular cell phenotypes in HIVAN. Since persistent tubular cell activation of NFκB has been reported in HIVAN, we now hypothesize that HIV may be contributing to tubular cell phenotype via lysophosphatidic acid (LPA) mediated downstream signaling. Interestingly, LPA and its receptors have also been implicated in the tubular interstitial cell fibrosis (TIF) and cyst formation in autosomal dominant polycystic kidney disease (PKD). Primary human proximal tubular cells (HRPTCs) were transduced with either empty vector (EV/HRPTCs), HIV (HIV/HRPTCs) or treated with LPA (LPA/HRPTC). Immunoelectrophoresis of HIV/HRPTCs and LPA/HRPTCs displayed enhanced expression of pro-fibrotic markers: a) fibronectin (2.25 fold), b) connective tissue growth factor (CTGF; 4.8 fold), c) α-smooth muscle actin (α-SMA; 12 fold), and d) collagen I (5.7 fold). HIV enhanced tubular cell phosphorylation of ILK-1, FAK, PI3K, Akt, ERKs and P38 MAPK. HIV increased tubular cell transcriptional binding activity of NF-κB; whereas, a LPA biosynthesis inhibitor (AACOCF3), a DAG kinase inhibitor, a LPA receptor blocker (Ki16425), a NF-κB inhibitor (PDTC) and NFκB-siRNA not only displayed downregulation of a NFκB activity but also showed attenuated expression of profibrotic/EMT genes in HIV milieu. These findings suggest that LPA could be contributing to HIV-induced tubular cell phenotype via NFκB activation in HIVAN.
Topics: AIDS-Associated Nephropathy; Actins; Cells, Cultured; Collagen Type I; Connective Tissue Growth Factor; Down-Regulation; Epithelial-Mesenchymal Transition; Fibronectins; Focal Adhesion Kinase 1; Gene Silencing; Genetic Vectors; Humans; Kidney Glomerulus; Kidney Tubules; Lysophospholipids; NF-kappa B; Phenotype; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Up-Regulation; Vimentin; p38 Mitogen-Activated Protein Kinases
PubMed: 26079546
DOI: 10.1016/j.yexmp.2015.06.004 -
Disease Models & Mechanisms Aug 2021People of recent sub-Saharan African ancestry develop kidney failure much more frequently than other groups. A large fraction of this disparity is due to two coding...
People of recent sub-Saharan African ancestry develop kidney failure much more frequently than other groups. A large fraction of this disparity is due to two coding sequence variants in the APOL1 gene. Inheriting two copies of these APOL1 risk variants, known as G1 and G2, causes high rates of focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy and hypertension-associated end-stage kidney disease. Disease risk follows a recessive mode of inheritance, which is puzzling given the considerable data that G1 and G2 are toxic gain-of-function variants. We developed coisogenic bacterial artificial chromosome (BAC) transgenic mice harboring either the wild-type (G0), G1 or G2 forms of human APOL1. Expression of interferon gamma (IFN-γ) via plasmid tail vein injection results in upregulation of APOL1 protein levels together with robust induction of heavy proteinuria and glomerulosclerosis in G1/G1 and G2/G2 but not G0/G0 mice. The disease phenotype was greater in G2/G2 mice. Neither heterozygous (G1/G0 or G2/G0) risk variant mice nor hemizygous (G1/-, G2/-) mice had significant kidney injury in response to IFN-γ, although the heterozygous mice had a greater proteinuric response than the hemizygous mice, suggesting that the lack of significant disease in humans heterozygous for G1 or G2 is not due to G0 rescue of G1 or G2 toxicity. Studies using additional mice (multicopy G2 and a non-isogenic G0 mouse) supported the notion that disease is largely a function of the level of risk variant APOL1 expression. Together, these findings shed light on the recessive nature of APOL1-nephropathy and present an important model for future studies.
Topics: AIDS-Associated Nephropathy; Animals; Apolipoprotein L1; Chromosomes, Artificial, Bacterial; Gain of Function Mutation; Genetic Predisposition to Disease; Humans; Mice; Mice, Transgenic
PubMed: 34350953
DOI: 10.1242/dmm.048952 -
Scandinavian Journal of Pain Jul 2020Background and aims The placebo response has been identified as one factor responsible for the lack of therapeutic trials with positive outcomes in neuropathic pain.... (Comparative Study)
Comparative Study Meta-Analysis
Background and aims The placebo response has been identified as one factor responsible for the lack of therapeutic trials with positive outcomes in neuropathic pain. Reviews have suggested that certain neuropathic pain conditions, including HIV-associated sensory neuropathy (HIV-SN), exhibit a greater placebo response than other neuropathic aetiologies. If true, such a finding could substantially affect clinical trial design and therapeutic developments for these conditions. This study aimed to identify any difference in placebo response between trials of systemic pharmacological intervention in HIV-SN and a comparable neuropathic condition, diabetic polyneuropathy (DPN) and to identify factors influencing the placebo response. Methods A systematic review search to identify randomised, double-blind studies of systemic pharmacological interventions for painful HIV-SN and DPN published between January 1966 and June 2019 was performed. A meta-analysis of the magnitude of placebo response and the proportion of placebo responders was conducted and compared between the two disease conditions. A meta-regression was used to assess for any study and participant characteristics that were associated with the placebo response. Only studies meeting a methodological quality threshold were included. Results Seventy-five trials were identified. There was no statistically significant difference in the proportion of placebo responders (HIV-SN = 0.35; versus DPN = 0.27, p = 0.129). The difference observed in the magnitude of the placebo response [pain reduction of 1.68 (1.47-1.88) DPN; 2.38 (1.87-2.98) in HIV-SN] was based on only 2 trials of HIV-SN and 35 of DPN. Potential factors influencing the placebo response such as psychological measures, were reported inconsistently. Conclusions We found no statistically significant difference in the placebo response rate between painful HIV-SN and DPN. Too few studies were available that reported the necessary information to clarify potential differences in the magnitude of placebo response or to elucidate parameters that could be contributing such differences. Implications The placebo response is one factor that may contribute to a lack of positive trials in neuropathic pain; some etiologies may display larger responses than others. This meta-analysis found no significant difference in placebo response between trials of HIV-associated sensory neuropathy and painful diabetic polyneuropathy, although limited data were available.
Topics: AIDS-Associated Nephropathy; Adult; Diabetic Neuropathies; Female; Humans; Male; Middle Aged; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 32106088
DOI: 10.1515/sjpain-2019-0152 -
PloS One 2022HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has...
HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has drawn increased attention because sodium wasting is common in hospitalized HIV/AIDS patients. We used viral protein R (Vpr)-transgenic mice to investigate the mechanisms whereby Vpr contributes to urinary sodium wasting. In phosphoenolpyruvate carboxykinase promoter-driven Vpr-transgenic mice, in situ hybridization showed that Vpr mRNA was expressed in all nephron segments, including the distal convoluted tubule. Vpr-transgenic mice, compared with wild-type littermates, markedly increased urinary sodium excretion, despite similar plasma renin activity and aldosterone levels. Kidneys from Vpr-transgenic mice also markedly reduced protein abundance of the Na+-Cl- cotransporter (NCC), while mineralocorticoid receptor (MR) protein expression level was unchanged. In African green monkey kidney cells, Vpr abrogated the aldosterone-mediated stimulation of MR transcriptional activity. Gene expression of Slc12a3 (NCC) in Vpr-transgenic mice was significantly lower compared with wild-type mice, assessed by both qRT-PCR and RNAScope in situ hybridization analysis. Chromatin immunoprecipitation assays identified multiple MR response elements (MRE), located from 5 kb upstream of the transcription start site and extending to the third exon of the SLC12A3 gene. Mutation of MRE and SP1 sites in the SLC12A3 promoter region abrogated the transcriptional responses to aldosterone and Vpr, indicating that functional MRE and SP1 are required for the SLC12A3 gene suppression in response to Vpr. Thus, Vpr attenuates MR transcriptional activity and inhibits Slc12a3 transcription in the distal convoluted tubule and contributes to salt wasting in Vpr-transgenic mice.
Topics: Aldosterone; Animals; Chlorocebus aethiops; Gene Products, vpr; HIV-1; Kidney Tubules, Distal; Mice; Mice, Transgenic; Phosphoenolpyruvate; RNA, Messenger; Receptors, Mineralocorticoid; Renin; Sodium; Sodium Chloride; Sodium Chloride Symporters; Solute Carrier Family 12, Member 3; Thiazides
PubMed: 36129874
DOI: 10.1371/journal.pone.0273313 -
American Journal of Nephrology 2015In African Americans (AAs), APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in an autosomal recessive pattern....
BACKGROUND
In African Americans (AAs), APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci, since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant, and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants.
METHODS
Re-sequencing was performed across a ∼275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant.
RESULTS
Sequencing identified 3,246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions. No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1,571 AA ESKD cases and 1,334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1,139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p = 0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes did not replicate this association.
CONCLUSION
Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.
Topics: AIDS-Associated Nephropathy; Adult; Black or African American; Aged; Anemia, Sickle Cell; Apolipoprotein L1; Apolipoproteins; Apolipoproteins L; Disease Progression; Female; Genetic Predisposition to Disease; Glomerulosclerosis, Focal Segmental; High-Throughput Nucleotide Sequencing; Humans; Hypertension, Renal; Kidney Failure, Chronic; Lipoproteins, HDL; Lupus Nephritis; Male; Middle Aged; Molecular Motor Proteins; Myosin Heavy Chains; Nephritis; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; Sequence Analysis, DNA
PubMed: 26343748
DOI: 10.1159/000439448 -
Journal of Neuroinflammation Mar 2016HIV-associated neurocognitive disorders (HAND) are a major complication in at least half of the infected population despite effective antiretroviral treatment and immune...
BACKGROUND
HIV-associated neurocognitive disorders (HAND) are a major complication in at least half of the infected population despite effective antiretroviral treatment and immune reconstitution. HIV-associated CNS damage is not correlated with active viral replication but instead is associated with mechanisms that regulate inflammation and neuronal compromise. Our data indicate that one of these mechanisms is mediated by gap junction channels and/or hemichannels. Normally, gap junction channels shutdown under inflammatory conditions, including viral diseases. However, HIV infection upregulates Connexin43 (Cx43) expression and maintains gap junctional communication by unknown mechanism(s).
METHODS
Human primary astrocytes were exposed to several HIV proteins as well as to HIV, and expression and function of Connexin43- and Connexin30-containing channels were determined by western blot, immunofluorescence, microinjection of a fluorescent tracer and chromatin immunoprecipitation (ChIP).
RESULTS
Here, we demonstrate that HIV infection increases Cx43 expression in vivo. HIV-tat, the transactivator of the virus, and no other HIV proteins tested, increases Cx43 expression and maintains functional gap junctional communication in human astrocytes. Cx43 upregulation is mediated by binding of the HIV-tat protein to the Cx43 promoter, but not to the Cx30 promoter, resulting in increased Cx43 messenger RNA (mRNA) and protein as well as gap junctional communication.
CONCLUSIONS
We propose that HIV-tat contributes to the spread of intracellular toxic signals generated in a few HIV-infected cells into surrounding uninfected cells by upregulating gap junctional communication. In the current antiretroviral era, where HIV replication is often completely suppressed, viral factors such as HIV-tat are still produced and released from infected cells. Thus, blocking the effects of HIV-tat could result in new strategies to reduce the damaging consequences of HIV infection of the CNS.
Topics: AIDS-Associated Nephropathy; Astrocytes; Brain; Cell Communication; Cells, Cultured; Chromatin Immunoprecipitation; Connexin 43; Gap Junctions; Humans; RNA, Small Interfering; tat Gene Products, Human Immunodeficiency Virus
PubMed: 26934876
DOI: 10.1186/s12974-016-0510-1