Impact of APOL1 polymorphism and IL-1β priming in the entry and persistence of HIV-1 in human podocytes

Mikulak, Joanna; Oriolo, Ferdinando; Portale, Federica; Tentorio, Paolo; Lan, Xiqian; Saleem, Moin A.; Skorecki, Karl; Singhal, Pravin C.; Mavilio, Domenico

doi:10.1186/s12977-016-0296-3

Cited by 38 publications

(40 citation statements)

References 74 publications

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“…In renal cells, one study reported HIV-1 infections of podocytes isolated from individuals with a highrisk and a low-risk genotype were not different with regard to supporting HIV infection (33). However, in another study, APOL1 overexpression in a commonly used podocyte cell line found HIV-1 uptake and persistence were greater with the risk variants compared with G0, suggesting anti-HIV functions observed in monocytes and T cells may also occur in podocytes and the risk variants may have a reduced ability to suppress infection (42).…”

Section: Loss-of-functionmentioning

confidence: 89%

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

Bruggeman

O’Toole

Sedor

2019

American Journal of Physiology-Renal Physiology

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The mechanism that explains the association of APOL1 variants with nondiabetic kidney diseases in African Americans remains unclear. Kidney disease risk is inherited as a recessive trait, and many studies investigating the intracellular function of APOL1 have indicated the APOL1 variants G1 and G2 are associated with cytotoxicity. Whether cytotoxicity results from the absence of a protective effect conferred by the G0 allele or is induced by a deleterious effect of variant allele expression has not be conclusively established. A central issue hampering basic biology studies is the lack of model systems that authentically replicate APOL1 expression patterns. APOL1 is present in humans and a few other primates and appears to have important functions in the kidney, as the kidney is the primary target for disease associated with the genetic variance. There have been no studies to date assessing the function of untagged APOL1 protein under native expression in human or primate kidney cells, and no studies have examined the heterozygous state, a disease-free condition in humans. A second major issue is the chronic kidney disease (CKD)-associated APOL1 variants are conditional mutations, where the disease-inducing function is only evident under the appropriate environmental stimulus. In addition, it is possible there may be more than one mechanism of pathogenesis that is dependent on the nature of the stressor or other genetic variabilities. Studies addressing the function of APOL1 and how the CKD-associated APOL1 variants cause kidney disease are challenging and remain to be fully investigated under conditions that faithfully model known human genetics and physiology.

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Section: Loss-of-functionmentioning

confidence: 89%

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

Bruggeman

O’Toole

Sedor

2019

American Journal of Physiology-Renal Physiology

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“…However, in the absence of such adverse milieus, it is considered that APOL1 expression may be dispensable to kidney health (19). Since LPS, TNF-␣, human immunodeficiency virus, and IFN-␥ have been reported to enhance expression of APOL1 in podocytes (23,24,27), these agents could be used to prevent downregulation of APOL1 in high-glucose milieu. However, these agents are phlogogenic de novo and would not be suitable in chronic kidney disease-carrying pre-existing inflammatory milieu.…”

Section: Discussionmentioning

confidence: 99%

“…Generation of a stable cell lines expressing APOL1G0 and vector. A stable cell line expressing APOL1G0 was generated by retroviral infection as described previously (27). Briefly, the open reading frame of APOL1G0 was cloned into the retroviral vector pBABE carrying resistance to puromycin.…”

Section: Methodsmentioning

confidence: 99%

Modulation of apolipoprotein L1-microRNA-193a axis prevents podocyte dedifferentiation in high-glucose milieu

Mishra

Ayasolla

Kumar

et al. 2018

American Journal of Physiology-Renal Physiology

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The loss of podocyte (PD) molecular phenotype is an important feature of diabetic podocytopathy. We hypothesized that high glucose (HG) induces dedifferentiation in differentiated podocytes (DPDs) through alterations in the apolipoprotein (APO) L1-microRNA (miR) 193a axis. HG-induced DPD dedifferentiation manifested in the form of downregulation of Wilms' tumor 1 (WT1) and upregulation of paired box 2 (PAX2) expression. WT1-silenced DPDs displayed enhanced expression of PAX2. Immunoprecipitation of DPD cellular lysates with anti-WT1 antibody revealed formation of WT1 repressor complexes containing Polycomb group proteins, enhancer of zeste homolog 2, menin, and DNA methyltransferase (DNMT1), whereas silencing of either WT1 or DNMT1 disrupted this complex with enhanced expression of PAX2. HG-induced DPD dedifferentiation was associated with a higher expression of miR193a, whereas inhibition of miR193a prevented DPD dedifferentiation in HG milieu. HG downregulated DPD expression of APOL1. miR193a-overexpressing DPDs displayed downregulation of APOL1 and enhanced expression of dedifferentiating markers; conversely, silencing of miR193a enhanced the expression of APOL1 and preserved DPD phenotype. Moreover, stably APOL1G0-overexpressing DPDs displayed the enhanced expression of WT1 but attenuated expression of miR193a; nonetheless, silencing of APOL1 reversed these effects. Since silencing of APOL1 enhanced miR193a expression as well as dedifferentiation in DPDs, it appears that downregulation of APOL1 contributed to dedifferentiation of DPDs through enhanced miR193a expression in HG milieu. Vitamin D receptor agonist downregulated miR193a, upregulated APOL1 expression, and prevented dedifferentiation of DPDs in HG milieu. These findings suggest that modulation of the APOL1-miR193a axis carries a potential to preserve DPD molecular phenotype in HG milieu.

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“…Most recently, Mikulak and colleagues studied the effect of APOL1 transfection on HIV infection of cultured podocytes (Mikulak et al 2016). The APOL1 G0 variant reduced viral accumulation, while APOL1 risk variants increased viral accumulation.…”

Section: Apol1 and The Molecular And Cellular Mechanisms Of Hivanmentioning

confidence: 99%

APOL1 Renal Risk Variants: Fertile Soil for HIV-Associated Nephropathy

Kopp

Heymann

Winkler

2017

Seminars in Nephrology

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Apolipoprotein L1 (APOL1) genetic variants are potent risk factors for glomerular disease, but one or more additional factors are required for expression of glomerular disease. Uncontrolled or poorly controlled HIV infection is the most potent susceptibility factor for APOL1 nephropathy that has been identified to date. APOL1 variants are associated with HIV-associated nephropathy (HIVAN), a podocyte disease, but not with HIV-immune complex disease, primarily a disease of the mesangium. The mechanism by which HIV brings out the latent glomerular disease risk remains to be defined. There are at least two classes of candidate mechanisms to explain the potent interaction between HIV-1 and APOL1. First, APOL1 variant proteins and HIV accessory proteins implicated in HIVAN may target the same or related intracellular pathways in podocytes. Recent data suggests roles for interleukin 1b and transcription factor EB (TFEB). Second, features of uncontrolled HIV-infection, including elevated circulating factors such as interferon, may drive APOL1 gene transcription or act upon podocytes in other ways. Deeper probing of APOL1-HIV interactions may yield insights that will aid understanding HIVAN, APOL1 nephropathy, and podocyte biology.

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Impact of APOL1 polymorphism and IL-1β priming in the entry and persistence of HIV-1 in human podocytes

Cited by 38 publications

References 74 publications

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

Modulation of apolipoprotein L1-microRNA-193a axis prevents podocyte dedifferentiation in high-glucose milieu

APOL1 Renal Risk Variants: Fertile Soil for HIV-Associated Nephropathy

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