APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8

Madhavan, Sethu M.; O’Toole, John F.; Konieczkowski, Martha; Barisoni, Laura; Thomas, David B.; Ganesan, Santhi; Bruggeman, Leslie A.; Buck, Matthias; Sedor, John R.

doi:10.1172/jci.insight.92581

Cited by 49 publications

(84 citation statements)

References 45 publications

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“…1C). Lack of tubule expression is consistent with our prior mRNA in situ hybridization results from human kidney which also did not find evidence of APOL1 expression in tubules (5). Also similar to humans, the BAC-APOL1 transgenic mice had abundant APOL1 in serum ( Fig.…”

Section: Resultssupporting

confidence: 90%

“…In the kidney, this circulating APOL1 protein was readily detected in blood trapped in vascular lumens (Supplemental Figure 2). Overall, there was no difference in the APOL1 expression patterns between the G0, G1, or G2 expressing mice (Supplemental Figure 2), similar to our previous studies in human biopsies from patients with different APOL1 genotypes (5,6,16).…”

Section: Resultssupporting

confidence: 88%

“…We and others had originally reported APOL1 protein is present in proximal tubules of normal and diseased subjects (4,6). However, our continuing work with other anti-APOL1 antibodies and subsequent studies using mRNA in situ hybridization indicated APOL1 was not expressed by proximal tubules (5). A remaining possibility is that APOL1 protein is filtered and reabsorbed, resulting in the appearance of APOL1 protein in proximal tubules.…”

Section: Discussionmentioning

confidence: 84%

“…Prior studies have minimized a causal role for the constitutively circulating APOL1 protein (1)(2)(3), thus efforts to understand kidney pathogenesis have focused on APOL1 expressed in renal cells. The APOL1 kidney expression pattern remains unclear with published discrepancies between immunohistochemistry and mRNA in situ hybridization results, most notably the abundant APOL1 protein observed in proximal tubule cells (4)(5)(6). In addition, since APOL1 is constitutively present in blood, it is unclear if APOL1 is filtered, especially in the setting of proteinuria, which could result in APOL1 protein reabsorption by the proximal tubule.…”

Section: Introductionmentioning

confidence: 99%

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APOL1 is not expressed in proximal tubules and is not filtered

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Madhavan

et al. 2019

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The kidney expression pattern of APOL1 was examined using both protein and mRNA in situ methods on APOL1 bacterial artificial chromosome transgenic mice, with and without proteinuria.APOL1 was detected in podocytes and endothelial cells of the kidney, but was not expressed in tubular epithelia, nor was plasma APOL1 protein filtered and reabsorbed by the proximal tubule. APOL1 expression in podocytes and endothelia should remain the focus for mechanistic studies of APOL1-mediated pathogenesis.

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

APOL1 is not expressed in proximal tubules and is not filtered

Blessing

Madhavan

et al. 2019

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“…[7][8][9][10][11] APOL1 is also expressed in some renal cells including the podocyte. [12][13][14] In HIVAN and mouse models of HIVAN, HIV-1 genes also are expressed in podocytes, [15][16][17][18][19][20][21][22] and HIV-1 gene expression in podocytes alone is sufficient to be disease-causing in mouse models. 23,24 Thus, HIVAN is an ideal disease to study the functional interaction of podocyte-expressed APOL1 with a known environmental trigger (HIV).…”

Section: Introductionmentioning

confidence: 99%

APOL1-G0protects podocytes in a mouse model of HIV-associated nephropathy

Bruggeman

Luo

et al. 2019

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Background: African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic kidney diseases (CKD) including HIV-associated nephropathy (HIVAN). APOL1 is expressed in renal cells, however, the pathogenic events that lead to renal cell damage and kidney disease are not fully understood. Methods:The podocyte function of APOL1-G0 versus APOL1-G2 in the setting of a known disease stressor was assessed using transgenic mouse models. Survival, renal pathology and function, and podocyte density were assessed in an intercross of a mouse model of HIVAN (Tg26) with two mouse models that express either APOL1-G0 or APOL1-G2 in podocytes. Results:Mice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that coexpressed APOL1-G0 and HIV had preserved podocyte numbers and densities, with fewer morphologic manifestations typical of HIVAN pathology. Podocyte losses and pathology in mice co-expressing APOL1-G2 and HIV were not significantly different from mice expressing only HIV. Podocyte hypertrophy, a known compensatory event to stress, was increased in the mice coexpressing HIV and APOL1-G0, but absent in the mice co-expressing HIV and APOL1-G2. Mortality and renal function tests were not significantly different between groups.Conclusions: APOL1-G0 expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This function appears to be absent with APOL1-G2 expression, suggesting APOL1-G2 is a loss-of-function variant.

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The Janus-faced functions of Apolipoproteins L in membrane dynamics

Pays

2024

Cell. Mol. Life Sci.

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The functions of human Apolipoproteins L (APOLs) are poorly understood, but involve diverse activities like lysis of bloodstream trypanosomes and intracellular bacteria, modulation of viral infection and induction of apoptosis, autophagy, and chronic kidney disease. Based on recent work, I propose that the basic function of APOLs is the control of membrane dynamics, at least in the Golgi and mitochondrion. Together with neuronal calcium sensor-1 (NCS1) and calneuron-1 (CALN1), APOL3 controls the activity of phosphatidylinositol-4-kinase-IIIB (PI4KB), involved in both Golgi and mitochondrion membrane fission. Whereas secreted APOL1 induces African trypanosome lysis through membrane permeabilization of the parasite mitochondrion, intracellular APOL1 conditions non-muscular myosin-2A (NM2A)-mediated transfer of PI4KB and APOL3 from the Golgi to the mitochondrion under conditions interfering with PI4KB-APOL3 interaction, such as APOL1 C-terminal variant expression or virus-induced inflammatory signalling. APOL3 controls mitophagy through complementary interactions with the membrane fission factor PI4KB and the membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). In mice, the basic APOL1 and APOL3 activities could be exerted by mAPOL9 and mAPOL8, respectively. Perspectives regarding the mechanism and treatment of APOL1-related kidney disease are discussed, as well as speculations on additional APOLs functions, such as APOL6 involvement in adipocyte membrane dynamics through interaction with myosin-10 (MYH10).

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APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8

Cited by 49 publications

References 45 publications

APOL1 is not expressed in proximal tubules and is not filtered

APOL1 is not expressed in proximal tubules and is not filtered

APOL1-G0protects podocytes in a mouse model of HIV-associated nephropathy

The Janus-faced functions of Apolipoproteins L in membrane dynamics

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