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JCI Insight Sep 2020We previously used global Hipk2-null mice in various models of kidney disease to demonstrate the central role of homeodomain-interacting protein kinase 2 (HIPK2) in...
We previously used global Hipk2-null mice in various models of kidney disease to demonstrate the central role of homeodomain-interacting protein kinase 2 (HIPK2) in renal fibrosis development. However, renal tubular epithelial cell-specific (RTEC-specific) HIPK2 function in renal fibrogenesis has yet to be determined. Here, we show that modulation of tubular HIPK2 expression and activity affects renal fibrosis development in vivo. The loss of HIPK2 expression in RTECs resulted in a marked diminution of renal fibrosis in unilateral ureteral obstruction (UUO) mouse models and HIV-associated nephropathy (HIVAN) mouse models, which was associated with the reduction of Smad3 activation and downstream expression of profibrotic markers. Conversely, WT HIPK2 overexpression in RTECs accentuated the extent of renal fibrosis in the setting of UUO, HIVAN, and folic acid-induced nephropathy in mice. Notably, kinase-dead HIPK2 mutant overexpression or administration of BT173, an allosteric inhibitor of HIPK2-Smad3 interaction, markedly attenuated the renal fibrosis in these mouse models of kidney disease, indicating that HIPK2 requires both the kinase activity and its interaction with Smad3 to promote TGF-β-mediated renal fibrosis. Together, these results establish an important RTEC-specific role of HIPK2 in kidney fibrosis and further substantiate the inhibition of HIPK2 as a therapeutic approach against renal fibrosis.
Topics: AIDS-Associated Nephropathy; Animals; Fibrosis; Humans; Kidney Tubules; Loss of Function Mutation; Mice; Mice, Inbred C57BL; Protein Serine-Threonine Kinases; Renal Insufficiency, Chronic; Smad3 Protein; Transforming Growth Factor beta
PubMed: 32701510
DOI: 10.1172/jci.insight.136004 -
Medicina (Kaunas, Lithuania) Dec 2022The Human Immunodeficiency Virus (HIV) is a highly morphic, retrovirus that rapidly evolves through mutation as well as recombination. Because of the immunocompromised...
The Human Immunodeficiency Virus (HIV) is a highly morphic, retrovirus that rapidly evolves through mutation as well as recombination. Because of the immunocompromised status in HIV patients, there is often a higher chance of acquiring different secondary infections followed by liver cirrhosis, hepatitis B & C, and HIV-associated nephropathy. The current study was conducted to see the prevalence of secondary infections, hematological and biochemical markers for liver and renal associated diseases, and to detect the envelope gene (GP41) in newly diagnosed HIV patients. A total of 37 samples were collected from HIV-positive patients registered in different hospital settings under the National AIDS control program. The collected samples were processed for hepatitis B, hepatitis C, hematological analysis, and biochemical analysis. To identify the envelope gene in newly diagnosed HIV patients, polymerase chain reaction (PCR) was performed using four gene-specific primers. The HIV infections were seen more in male as compared to females. A significant decrease in complete blood count was observed in HIV patients when compared to healthy individuals. There was a significant increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine observed in HIV patients. No significant difference was observed in alkaline phosphatase (ALP), total bilirubin, and albumin levels when compared to healthy control. Anemia was observed in 59.4% of HIV patients. A total of three (8.1%) patients were found to be co-infected with hepatitis B and one (2.7 %) was co-infected with hepatitis C. Out of these 37 tested samples, a total of four showed the successful amplification of the envelope gene. This study provides platform for the health care facilitators to regularly monitor the signs, symptoms and clinical biomarkers of HIV-associated infections to prevent toxicity at an early stage to improve the quality of life (QoL) and minimize the mortality rate in HIV patients. Envelope gene mutating frequently results in drug resistance, and thus future research on polymorphism analysis will reveal points of substitutions to improve drug designing.
Topics: Female; Humans; Male; HIV Infections; HIV; Quality of Life; Coinfection; Hepatitis B; Hepatitis C; Hepacivirus; Prevalence; Biomarkers
PubMed: 36676716
DOI: 10.3390/medicina59010093 -
PloS One 2021HIV-positive persons of African descent are disproportionately affected by chronic kidney disease (CKD). Deterioration to end-stage kidney disease (ESKD) also occurs in...
BACKGROUND
HIV-positive persons of African descent are disproportionately affected by chronic kidney disease (CKD). Deterioration to end-stage kidney disease (ESKD) also occurs in this population at a higher frequency. There remains a lot to learn about the genetic susceptibility to CKD in HIV positive patients, and the pathophysiology of progression to ESKD.
OBJECTIVES
We will conduct an exploratory genotype-phenotype study in HIV-positive persons with CKD in Aminu Kano Teaching Hospital, Nigeria, to determine blood-based differential gene expression biomarkers in different kidney risk groups according to the KDIGO 2012 criteria.
METHODS
We will consecutively screen 150 HIV-positive adults (≥18 years of age) attending the HIV clinic of Aminu Kano Teaching Hospital, Kano, Nigeria, for CKD based on proteinuria and elevation of estimated glomerular filtration rate. Among these, two separate groups of 16 eligible participants each (n = 32) will be selected in the four (4) KDIGO 2012 kidney risk categories. The groups will be matched for age, sex, viral suppression level and antiretroviral (ARV) regimen. In the first group (n = 16), we will determine differential gene expression markers in peripheral blood mononuclear cells using mRNA-sequencing (RNA-Seq). We will validate the differential expression markers in the second group (n = 16) using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Using a systems-based approach, we will construct, visualize and analyze gene-gene interaction networks to determine the potential biological roles of identified differential expression markers based on published literature and publicly available databases.
RESULTS
Our exploratory study will provide valuable information on the potential roles of differential expression biomarkers in the pathophysiology of HIV-associated kidney disease by identifying novel biomarkers in different risk categories of CKD in a sub-Saharan African population. The results of this study will provide the basis for population-based genome-wide association studies to guide future personalized medicine approaches.
CONCLUSION
Validated biomarkers can be potential targets for the development of stage-specific therapeutic interventions, an essential paradigm in precision medicine.
Topics: AIDS-Associated Nephropathy; Africa South of the Sahara; Biomarkers; Black People; Disease Progression; Genetic Association Studies; Genetic Predisposition to Disease; Glomerular Filtration Rate; Humans; Leukocytes, Mononuclear; Polymorphism, Single Nucleotide; RNA-Seq
PubMed: 33822824
DOI: 10.1371/journal.pone.0249567 -
Journal of Clinical Medicine Sep 2019BK polyomavirus (BKPyV), or BKV infection, is ubiquitous and usually non-pathogenic, with subclinical infections in 80-90% of adults worldwide. BKV infection is often... (Review)
Review
BK polyomavirus (BKPyV), or BKV infection, is ubiquitous and usually non-pathogenic, with subclinical infections in 80-90% of adults worldwide. BKV infection is often associated with pathology in immunocompromised individuals. BKV infection often is associated with renal impairment, including ureteral stenosis, hemorrhagic cystitis, and nephropathy. BKV infection is less commonly associated with pneumonitis, retinitis, liver disease, and meningoencephalitis. BKV is known to replicate, establish latency, undergo reactivation, and induce clinical pathology in renal tubular epithelial cells. However, recent in vitro studies support the notion that BKV has expanded tropism-targeting glomerular parenchymal cells of the human kidney, which could impact glomerular function, enhance inflammation, and serve as viral reservoirs for reactivation from latency during immunosuppression. The implications of BKV expanded tropism in the glomerulus, and how specific host and viral factors that would contribute to glomerular inflammation, cytolysis, and renal fibrosis are related to BKV associated nephropathy (BKVAN), have not been explored. The pathogenesis of BKV in human glomerular parenchymal cells is poorly understood. In this review, I examine target cell populations for BKV infectivity in the human glomerulus. Specifically, I explore the implications of BKV expanded tropism in the glomerulus with regard viral entry, replication, and dissemination via cell types exposed to BKV trafficking in glomerulus. I also describe cellular targets shown to be permissive in vitro and in vivo for BKV infection and lytic replication, the potential role that glomerular parenchymal cells play in BKV latency and/or reactivation after immunosuppression, and the rare occurrence of BKV pathology in glomerular parenchymal cells in patients with BKVAN.
PubMed: 31533282
DOI: 10.3390/jcm8091477 -
BioRxiv : the Preprint Server For... Nov 2023Hyponatremia and salt wasting is a common occurance in patients with HIV/AIDS, however, the understanding of its contributing factors is limited. HIV viral protein R...
Hyponatremia and salt wasting is a common occurance in patients with HIV/AIDS, however, the understanding of its contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the expression level of the gene, encoding the Na-Cl cotransporter, which is responsible for sodium reabsorption in distal nephron segments, we performed single-nucleus RNA sequencing of kidney cortices from three wild-type (WT) and three Vpr-transgenic (Vpr Tg) mice. The results showed that the percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05), and that in Vpr Tg mice, expression was not different in DCT cell cluster. The DCT1 subcluster had fewer cells in Vpr Tg mice compared with WT (P < 0.01). Immunohistochemistry demonstrated fewer DCT1 segments in Vpr Tg mice. Differential gene expression analysis comparing Vpr Tg and WT in the DCT cluster showed , an inhibitor of apoptosis, to be the most downregulated gene. These observations demonstrate that the salt-wasting effect of Vpr in Vpr Tg mice is mediated by loss of DCT1 segments via apoptosis dysregulation.
PubMed: 36945458
DOI: 10.1101/2023.02.02.526686 -
Frontiers in Endocrinology 2021Globally, nearly 40 percent of all diabetic patients develop serious diabetic kidney disease (DKD). The identification of the potential early-stage biomarkers and...
Globally, nearly 40 percent of all diabetic patients develop serious diabetic kidney disease (DKD). The identification of the potential early-stage biomarkers and elucidation of their underlying molecular mechanisms in DKD are required. In this study, we performed integrated bioinformatics analysis on the expression profiles GSE111154, GSE30528 and GSE30529 associated with early diabetic nephropathy (EDN), glomerular DKD (GDKD) and tubular DKD (TDKD), respectively. A total of 1,241, 318 and 280 differentially expressed genes (DEGs) were identified for GSE30258, GSE30529, and GSE111154 respectively. Subsequently, 280 upregulated and 27 downregulated DEGs shared between the three GSE datasets were identified. Further analysis of the gene expression levels conducted on the hub genes revealed SPARC (Secreted Protein Acidic And Cysteine Rich), POSTN (periostin), LUM (Lumican), KNG1 (Kininogen 1), FN1 (Fibronectin 1), VCAN (Versican) and PTPRO (Protein Tyrosine Phosphatase Receptor Type O) having potential roles in DKD progression. FN1, LUM and VCAN were identified as upregulated genes for GDKD whereas the downregulation of PTPRO was associated with all three diseases. Both POSTN and SPARC were identified as the overexpressed putative biomarkers whereas KNG1 was found as downregulated in TDKD. Additionally, we also identified two drugs, namely pidorubicine, a topoisomerase inhibitor (LINCS ID- BRD-K04548931) and Polo-like kinase inhibitor (LINCS ID- BRD-K41652870) having the validated role in reversing the differential gene expression patterns observed in the three GSE datasets used. Collectively, this study aids in the understanding of the molecular drivers, critical genes and pathways that underlie DKD initiation and progression.
Topics: Computational Biology; Datasets as Topic; Diabetic Nephropathies; Drug Evaluation, Preclinical; Gene Expression Profiling; Gene Ontology; Gene Regulatory Networks; Genetic Association Studies; High-Throughput Screening Assays; Humans; Protein Interaction Maps; Systems Integration; Transcriptome
PubMed: 34557161
DOI: 10.3389/fendo.2021.721202 -
Journal of the American Society of... Jan 2022To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS that often arises in the setting of viral infections, we performed a genome-wide...
BACKGROUND
To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS that often arises in the setting of viral infections, we performed a genome-wide association study (GWAS) among inbred mouse strains using a murine model of HIV-1 associated nephropathy (HIVAN).
METHODS
We first generated F1 hybrids between HIV-1 transgenic mice on the FVB/NJ background and 20 inbred laboratory strains. Analysis of histology, BUN, and urinary NGAL demonstrated marked phenotypic variation among the transgenic F1 hybrids, providing strong evidence for host genetic factors in the predisposition to nephropathy. A GWAS in 365 transgenic F1 hybrids generated from these 20 inbred strains was performed.
RESULTS
We identified a genome-wide significant locus on chromosome 13-C3 and multiple additional suggestive loci. Crossannotation of the Chr. 13 locus, including single-cell transcriptomic analysis of wildtype and HIV-1 transgenic mouse kidneys, nominated as the most likely candidate gene. is highly expressed in podocytes, encodes a transcriptional cofactor that interacts with LDB1 and LMX1B, which are both previously implicated in FSGS. Consistent with these data, older null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis, and inflammation, similar to the HIVAN mouse model.
CONCLUSIONS
These findings demonstrate the utility of GWAS in mice to uncover host genetic factors for rare kidney traits and suggest as susceptibility gene for HIVAN, potentially acting the LDB1-LMX1B transcriptional network.
Topics: AIDS-Associated Nephropathy; Animals; DNA-Binding Proteins; Disease Models, Animal; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Glomerulosclerosis, Focal Segmental; Male; Mice; Mice, Transgenic
PubMed: 34893534
DOI: 10.1681/ASN.2021040543 -
BMC Nephrology Sep 2021HIV subjects have several kidney pathologies, like HIV-associated nephropathy or antiretroviral therapy injury, among others. The global prevalence of Chronic Kidney...
BACKGROUND
HIV subjects have several kidney pathologies, like HIV-associated nephropathy or antiretroviral therapy injury, among others. The global prevalence of Chronic Kidney Disease (CKD) is 8-16%; however, in HIV subjects, the prevalence varies between geographic regions (2-38%). The aim was to determine the prevalence of CKD and identify the associated risk factors.
METHODS
A longitudinal descriptive study was carried out at the 'Hospital Civil de Guadalajara' Feb'18 - Jan'19. Basal clinical, demographic, opportunistic infections (OI), and laboratory data were obtained at months 0 and 3; inclusion criteria were ≥ 18 years old, naïve HIV + , urine albumin/creatinine ratio, serum creatinine & urine test, and signed informed consent. Descriptive and multiple logistic regression statistical analyses were made.
RESULTS
One hundred twenty subjects were included; 92.5% were male, 33 ± 9.5 years, 60% consumed tobacco, 73% alcohol, and 59% some type of drug. The CKD prevalence was 15.8%. CKD patients had a higher risk of hepatitis C virus coinfection, Relative Risk (RR):5.9; HCV infection, RR:4.3; ≥ 30 years old, RR:3.9; C clinical-stage, RR:3.5; CD4 T cells count < 200 cells/μL, RR: 2.4; and HIV-1 viral load ≥ 100,000 cop/mL, RR: 2.7.
CONCLUSIONS
Our study showed a higher CKD prevalence in patients with HIV; higher CKD development with coinfections as Hepatitis C Virus and Mycobacterium tuberculosis. The identification and prompt management of CKD and coinfections should be considered to avoid the progression and to delay renal replacement therapy as long as possible.
Topics: AIDS-Associated Nephropathy; Adult; CD4 Lymphocyte Count; CD4-CD8 Ratio; Coinfection; Female; HIV Seropositivity; HIV-1; Humans; Male; Mexico; Prevalence; Renal Insufficiency, Chronic; Risk Factors; Viral Load
PubMed: 34556049
DOI: 10.1186/s12882-021-02526-4 -
Transplant Infectious Disease : An... Oct 2020We report a case of a 50-year-old male with a history of HIV and kidney transplant who presented with SARS-CoV-2. We also present a review of COVID-19 cases in kidney... (Review)
Review
We report a case of a 50-year-old male with a history of HIV and kidney transplant who presented with SARS-CoV-2. We also present a review of COVID-19 cases in kidney transplant recipients.
Topics: AIDS-Associated Nephropathy; Antirheumatic Agents; COVID-19; COVID-19 Nucleic Acid Testing; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; RNA, Viral; SARS-CoV-2; Transplant Recipients
PubMed: 32453483
DOI: 10.1111/tid.13338 -
Nephrology, Dialysis, Transplantation :... Feb 2021Chronic kidney disease (CKD) is a common cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals. Among the HIV-related kidney...
BACKGROUND
Chronic kidney disease (CKD) is a common cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals. Among the HIV-related kidney diseases, HIV-associated nephropathy (HIVAN) is a rapidly progressive renal disease characterized by collapsing focal glomerulosclerosis (GS), microcystic tubular dilation, interstitial inflammation and fibrosis. Although the incidence of end-stage renal disease due to HIVAN has dramatically decreased with the widespread use of antiretroviral therapy, the prevalence of CKD continues to increase in HIV-positive individuals. Recent studies have highlighted the role of apoptosis signal-regulating kinase 1 (ASK1) in driving kidney disease progression through the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase and selective ASK-1 inhibitor GS-444217 was recently shown to reduce kidney injury and disease progression in various experimental models. Therefore we examined the efficacy of ASK1 antagonism by GS-444217 in the attenuation of HIVAN in Tg26 mice.
METHODS
GS-444217-supplemented rodent chow was administered in Tg26 mice at 4 weeks of age when mild GS and proteinuria were already established. After 6 weeks of treatment, the kidney function assessment and histological analyses were performed and compared between age- and gender-matched control Tg26 and GS-444217-treated Tg26 mice.
RESULTS
GS-444217 attenuated the development of GS, podocyte loss, tubular injury, interstitial inflammation and renal fibrosis in Tg26 mice. These improvements were accompanied by a marked reduction in albuminuria and improved renal function. Taken together, GS-4442217 attenuated the full spectrum of HIVAN pathology in Tg26 mice.
CONCLUSIONS
ASK1 signaling cascade is central to the development of HIVAN in Tg26 mice. Our results suggest that the select inhibition of ASK1 could be a potential adjunctive therapy for the treatment of HIVAN.
Topics: AIDS-Associated Nephropathy; Animals; Disease Models, Animal; Fibrosis; Inflammation; MAP Kinase Kinase Kinase 5; Mice; Mice, Transgenic; Protein Kinase Inhibitors; Proteinuria
PubMed: 33097961
DOI: 10.1093/ndt/gfaa198