Disease relevance of Hivan1

• HIV-1-associated nephropathy (HIVAN) is a major complication of HIV-1 infection with distinct pathologic features [1].
• To confirm a direct effect of HIV expression on the production of HIVAN, we transplanted kidneys between normal and transgenic mice [2].
• HIV-associated nephropathy (HIVAN) is a progressive glomerular and tubular disease that is increasingly common in AIDS patients and one of the leading causes of end stage renal disease in African Americans [2].
• A major unresolved issue in the pathogenesis of HIVAN is whether the kidney disease is due to renal cell infection or a "bystander" phenomenon mediated by systemically dysregulated cytokines [2].
• Human immunodeficiency virus-associated nephropathy (HIVAN) affects up to 10% of HIV-positive black adults and children and is the leading cause of renal disease in infected individuals [3].

High impact information on Hivan1

• Both phospho-MAPK1,2 and phospho-Stat3 staining increased in podocytes of kidneys from HIV-1 transgenic mice compared with their littermates and in podocytes of kidneys from HIVAN patients compared with HIV patients with non-HIVAN kidney diseases or non-HIV patients with idiopathic FSGS, classic FSGS, or minimal-change disease [4].
• In collapsing focal segmental glomerulosclerosis (FSGS) of HIV-associated nephropathy (HIVAN), podocytes exhibit a high proliferation rate and loss of differentiation markers [4].
• Using two different experimental approaches, we demonstrate a direct effect of transgene expression on the development of HIVAN in the mouse [2].
• These findings demonstrate a strong genetic influence on HIVAN and demonstrate a major renal disease susceptibility locus on mouse chromosome 3A1-3 [1].
• Introduction of the HIV-1 genome into mice results in a renal disease with all of the histologic and clinical hallmarks of HIVAN on the FVB/N genetic background (TgFVB) [1].

Chemical compound and disease context of Hivan1

• Microcyst formation and HIV-1 gene expression occur in multiple nephron segments in HIV-associated nephropathy [5].
• To address whether flavopiridol could ameliorate HIV-induced renal disease, we utilized a well-established HIV-1 NL4-3 transgenic mouse model of HIVAN [6].
• Treatment with angiotensin-converting enzyme inhibitors may avert progression of HIVAN to end-stage kidney disease and result in superior patient and kidney survival as compared with untreated patients [7].

Biological context of Hivan1

• Although apoptotic cell death in HIVAN has been well documented, the mechanism for HIV-induced apoptosis is poorly understood [8].
• Therefore, proliferation induced by HIV-1 gene expression is likely to play a key role in the pathogenesis of HIVAN [3].
• DESIGN: Podocytes are highly differentiated non-dividing cells in the normal glomerulus, however, they undergo dedifferentiation and acquire a proliferative phenotype in HIVAN patients, in HIV-transgenic mice and if infected by HIV-1 in vitro [9].
• In addition, the expression level of a transfected NF-kappaB reporter plasmid was significantly higher in HIVAN podocytes [10].
• METHODS: The pathogenesis, epidemiology, and treatment options for HIVAN are discussed [11].

Anatomical context of Hivan1

• The immunohistochemical staining pattern of podocan protein in normal kidney glomeruli was consistent with that of the glomerular basement membrane, and staining was markedly increased in sclerotic glomerular lesions in the transgenic HIVAN model [12].
• HIV-1 has recently been shown to infect renal tubular epithelial cells in patients with HIVAN [5].
• It was demonstrated that HIV-1 mRNA is expressed in renal epithelium of the transgenic mouse and in patients with HIVAN, suggesting a direct role for HIV-1 in disease pathogenesis in both humans and the murine model [3].
• Protease inhibitors modulate apoptosis in mesangial cells derived from a mouse model of HIVAN [13].
• These results demonstrate that the mechanical properties of WT and HIVAN podocytes are markedly different in a manner that is consistent with differences in the composition and arrangement of their cytoskeletons [14].

Associations of Hivan1 with chemical compounds

• Podocan, a novel small leucine-rich repeat protein expressed in the sclerotic glomerular lesion of experimental HIV-associated nephropathy [12].
• Renal parenchymal injury in HIV-associated nephropathy (HIVAN) is characterized by epithelial proliferation, dedifferentiation, and apoptosis along the entire length of the nephron [8].
• These data validate recent nonrandomized studies of captopril in HIV-infected patients, and suggest that an angiotensin-converting enzyme substrate is an important mediator in HIVAN [15].
• A randomized placebo-controlled trial of captopril in HIVAN may be warranted [15].
• These transgenic mice developed renal injury similar to HIVAN when treated with doxycycline for 8 to 12 wk [16].

Other interactions of Hivan1

• NF-kappaB regulates Fas-mediated apoptosis in HIV-associated nephropathy [8].
• In cultured podocytes, cross-linking of the Fas receptor to mimic ligand binding induced caspase 8 activity and apoptosis in both normal and HIVAN podocytes [8].
• The purpose of this study was to determine whether circulating FGF-2 may play a role in the pathogenesis of HIVAN by increasing the renal recruitment and attachment of HIV-infected mononuclear cells to renal epithelial cells [17].
• These data suggest that nephron reduction exaggerates podocyte injury and subsequent glomerulosclerosis, possibly through glomerular hypertension, in the mouse model of HIVAN [16].
• Thus, suppression of HIV-1 transcription by selective cyclin-dependent kinase-9 inhibitors may be a useful therapeutic strategy for the treatment of HIVAN [18].

Analytical, diagnostic and therapeutic context of Hivan1

• The availability of these small animal models for the study of HIV-related syndromes including KS, epidermal proliferative lesions, HIV-associated nephropathy, AIDS-related growth failure and cachexia may well facilitate the development of novel therapies for these complications [19].
• In these studies, immunohistochemistry for tubular segment-specific markers and mRNA in situ hybridization for HIV-1 was used to determine which tubular segments develop microcysts and which segments express HIV-1 in the kidneys of transgenic mice and patients with HIVAN [5].
• Atomic force microscopy demonstrated that the WT cells had a stiffness of 17 kPa, whereas the value for the HIVAN cells was 4 kPa [14].
• Microarray analysis showed that 82% of the dysregulated genes in HIVAN kidney were normalized to control levels by flavopiridol, whereas continued dysregulation of most of the remaining 18% was attributable to an effect from flavopiridol alone [6].
• In these studies, we used oligonucleotide microarrays to identify differentially expressed genes in renal tubular epithelial cells from a patient with HIVAN at three time points after infection with vesicular stomatitis virus-pseudotyped gag/pol-deleted HIV-1 [20].

References