scholarly journals Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease

2021 ◽  
Vol 14 (8) ◽  
Author(s):  
Gizelle M. McCarthy ◽  
Angelo Blasio ◽  
Olivia G. Donovan ◽  
Lena B. Schaller ◽  
Althea Bock-Hughes ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Risk ◽  
Large Fraction ◽  
African Ancestry ◽  
Kidney Injury ◽  
Artificial Chromosome ◽  
Gain Of Function ◽  
Risk Variant ◽  
Protein Levels ◽  
Ifn Γ

ABSTRACT 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.

scholarly journals Variation inAPOL1Contributes to Ancestry-Level Differences in HDLc-Kidney Function Association

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Amy Rebecca Bentley ◽  
Ayo P. Doumatey ◽  
Guanjie Chen ◽  
Hanxia Huang ◽  
Jie Zhou ◽  
...  
Keyword(s):  
African Americans ◽  
Kidney Disease ◽  
Disease Risk ◽  
African Ancestry ◽  
Gene Encoding ◽  
Risk Variant ◽  
European Americans ◽  
Nationally Representative ◽  
High Density Cholesterol

Low levels of high-density cholesterol (HDLc) accompany chronic kidney disease, but the association between HDLc and the estimated glomerular filtration rate (eGFR) in the general population is unclear. We investigated the HDLc-eGFR association in nondiabetic Han Chinese (HC,n=1100), West Africans (WA,n=1497), and African Americans (AA,n=1539). There were significant differences by ancestry: HDLc was positively associated with eGFR in HC (β=0.13,P<0.0001), but negatively associated among African ancestry populations (WA: −0.19,P<0.0001; AA: −0.09,P=0.02). These differences were also seen in nationally-representative NHANES data (among European Americans: 0.09,P=0.005; among African Americans −0.14,P=0.03). To further explore the findings in African ancestry populations, we investigated the role of an African ancestry-specific nephropathy risk variant, rs73885319, in the gene encoding HDL-associated APOL1. Among AA, an inverse HDLc-eGFR association was observed only with the risk genotype (−0.38 versus 0.001;P=0.03). This interaction was not seen in WA. In summary, counter to expectation, an inverse HDLc-eGFR association was observed among those of African ancestry. Given theAPOL1× HDLc interaction among AA, genetic factors may contribute to this paradoxical association. Notably, these findings suggest that the unexplained mechanism by whichAPOL1affects kidney-disease risk may involve HDLc.

scholarly journals APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases

2015 ◽  
Vol 113 (4) ◽  
pp. 830-837 ◽  
Author(s):  
Opeyemi A. Olabisi ◽  
Jia-Yue Zhang ◽  
Lynn VerPlank ◽  
Nathan Zahler ◽  
Salvatore DiBartolo ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Protein Kinases ◽  
Intracellular Signaling ◽  
Cultured Cells ◽  
Disease Risk ◽  
African Ancestry ◽  
High Rate ◽  
Cell Swelling ◽  
Risk Variant ◽  
Risk Variants

Two specific genetic variants of the apolipoprotein L1 (APOL1) gene are responsible for the high rate of kidney disease in people of recent African ancestry. Expression in cultured cells of these APOL1 risk variants, commonly referred to as G1 and G2, results in significant cytotoxicity. The underlying mechanism of this cytotoxicity is poorly understood. We hypothesized that this cytotoxicity is mediated by APOL1 risk variant-induced dysregulation of intracellular signaling relevant for cell survival. To test this hypothesis, we conditionally expressed WT human APOL1 (G0), the APOL1 G1 variant, or the APOL1 G2 variant in human embryonic kidney cells (T-REx-293) using a tetracycline-mediated (Tet-On) system. We found that expression of either G1 or G2 APOL1 variants increased apparent cell swelling and cell death compared with G0-expressing cells. These manifestations of cytotoxicity were preceded by G1 or G2 APOL1-induced net efflux of intracellular potassium as measured by X-ray fluorescence, resulting in the activation of stress-activated protein kinases (SAPKs), p38 MAPK, and JNK. Prevention of net K+ efflux inhibited activation of these SAPKs by APOL1 G1 or G2. Furthermore, inhibition of SAPK signaling and inhibition of net K+ efflux abrogated cytotoxicity associated with expression of APOL1 risk variants. These findings in cell culture raise the possibility that nephrotoxicity of APOL1 risk variants may be mediated by APOL1 risk variant-induced net loss of intracellular K+ and subsequent induction of stress-activated protein kinase pathways.

scholarly journals Associations of Urine Biomarkers with Kidney Function Decline in HIV-Infected and Uninfected Men

2019 ◽  
Vol 50 (5) ◽  
pp. 401-410 ◽  
Author(s):  
Simon B. Ascher ◽  
Rebecca Scherzer ◽  
Michelle M. Estrella ◽  
Michael G. Shlipak ◽  
Derek K. Ng ◽  
...  
Keyword(s):  
Risk Factors ◽  
Kidney Disease ◽  
Kidney Function ◽  
Disease Risk ◽  
Kidney Injury ◽  
Procollagen Type ◽  
Urine Albumin ◽  
Urine Biomarkers ◽  
Increased Risk ◽  
Egfr Decline

Background: HIV-infected (HIV+) persons are at increased risk of chronic kidney disease, but serum creatinine does not detect early losses in kidney function. We hypothesized that urine biomarkers of kidney damage would be associated with subsequent changes in kidney function in a contemporary cohort of HIV+ and HIV-uninfected (HIV–) men. Methods: In the Multicenter AIDS Cohort Study, we measured baseline urine concentrations of 5 biomarkers from 2009 to 2011 in 860 HIV+ and 337 HIV– men: albumin, alpha-1-microglobulin (α1m), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and procollagen type III N-terminal propeptide (PIIINP). We evaluated associations of urine biomarker concentrations with annual changes in estimated glomerular filtration rate (eGFR) using multivariable linear mixed models adjusted for demographics, traditional kidney disease risk factors, HIV-related risk factors, and baseline eGFR. Results: Over a median follow-up of 4.8 years, the average annual eGFR decline was 1.42 mL/min/1.73 m2/year in HIV+ men and 1.22 mL/min/1.73 m2/year in HIV– men. Among HIV+ men, the highest vs. lowest tertiles of albumin (–1.78 mL/min/1.73 m2/year, 95% CI –3.47 to –0.09) and α1m (–2.43 mL/min/1.73 m2/year, 95% CI –4.14 to –0.73) were each associated with faster annual eGFR declines after multivariable adjustment. Among HIV– men, the highest vs. lowest tertile of α1m (–2.49 mL/min/1.73 m2/year, 95% CI –4.48 to –0.50) was independently associated with faster annual eGFR decline. Urine IL-18, KIM-1, and PIIINP showed no independent associations with eGFR decline, regardless of HIV serostatus. Conclusions: Among HIV+ men, higher urine albumin and α1m are associated with subsequent declines in kidney function, independent of eGFR.

scholarly journals Recruitment of APOL1 kidney disease risk variants to lipid droplets attenuates cell toxicity

2019 ◽  
Vol 116 (9) ◽  
pp. 3712-3721 ◽  
Author(s):  
Justin Chun ◽  
Jia-Yue Zhang ◽  
Maris S. Wilkins ◽  
Balajikarthick Subramanian ◽  
Cristian Riella ◽  
...  
Keyword(s):  
Cell Death ◽  
Kidney Disease ◽  
Lipid Droplets ◽  
Disease Risk ◽  
Significant Proportion ◽  
Autophagic Flux ◽  
Cell Toxicity ◽  
Risk Variant ◽  
Risk Variants ◽  
Increased Risk

Two coding variants in the apolipoprotein L1 (APOL1) gene (termed G1 and G2) are strongly associated with increased risk of nondiabetic kidney disease in people of recent African ancestry. The mechanisms by which the risk variants cause kidney damage, although not well-understood, are believed to involve injury to glomerular podocytes. The intracellular localization and function of APOL1 in podocytes remain unclear, with recent studies suggesting possible roles in the endoplasmic reticulum (ER), mitochondria, endosomes, lysosomes, and autophagosomes. Here, we demonstrate that APOL1 also localizes to intracellular lipid droplets (LDs). While a large fraction of risk variant APOL1 (G1 and G2) localizes to the ER, a significant proportion of wild-type APOL1 (G0) localizes to LDs. APOL1 transiently interacts with numerous organelles, including the ER, mitochondria, and endosomes. Treatment of cells that promote LD formation with oleic acid shifted the localization of G1 and G2 from the ER to LDs, with accompanying reduction of autophagic flux and cytotoxicity. Coexpression of G0 APOL1 with risk variant APOL1 enabled recruitment of G1 and G2 from the ER to LDs, accompanied by reduced cell death. The ability of G0 APOL1 to recruit risk variant APOL1 to LDs may help explain the recessive pattern of kidney disease inheritance. These studies establish APOL1 as a bona fide LD-associated protein, and reveal that recruitment of risk variant APOL1 to LDs reduces cell toxicity, autophagic flux, and cell death. Thus, interventions that divert APOL1 risk variants to LDs may serve as a novel therapeutic strategy to alleviate their cytotoxic effects.

scholarly journals UBD modifies APOL1-induced kidney disease risk

2018 ◽  
Vol 115 (13) ◽  
pp. 3446-3451 ◽  
Author(s):  
Jia-Yue Zhang ◽  
Minxian Wang ◽  
Lei Tian ◽  
Giulio Genovese ◽  
Paul Yan ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Risk ◽  
African Ancestry ◽  
Genetic Modifiers ◽  
Cell Toxicity ◽  
Mapping Study ◽  
Risk Alleles ◽  
Inflammatory Stimuli ◽  
Coding Variants ◽  
Apolipoprotein L1

People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1. We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.

scholarly journals Overexpression of PKD1 Causes Polycystic Kidney Disease

2006 ◽  
Vol 26 (4) ◽  
pp. 1538-1548 ◽  
Author(s):  
Caroline Thivierge ◽  
Almira Kurbegovic ◽  
Martin Couillard ◽  
Richard Guillaume ◽  
Olivier Coté ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Artificial Chromosome ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Gain Of Function ◽  
Downstream Effector ◽  
Transgenic Lines ◽  
Autosomal Dominant Polycystic Kidney

ABSTRACT The pathogenetic mechanisms underlying autosomal dominant polycystic kidney disease (ADPKD) remain to be elucidated. While there is evidence that Pkd1 gene haploinsufficiency and loss of heterozygosity can cause cyst formation in mice, paradoxically high levels of Pkd1 expression have been detected in the kidneys of ADPKD patients. To determine whether Pkd1 gain of function can be a pathogenetic process, a Pkd1 bacterial artificial chromosome (Pkd1-BAC) was modified by homologous recombination to solely target a sustained Pkd1 expression preferentially to the adult kidney. Several transgenic lines were generated that specifically overexpressed the Pkd1 transgene in the kidneys 2- to 15-fold over Pkd1 endogenous levels. All transgenic mice reproducibly developed tubular and glomerular cysts and renal insufficiency and died of renal failure. This model demonstrates that overexpression of wild-type Pkd1 alone is sufficient to trigger cystogenesis resembling human ADPKD. Our results also uncovered a striking increased renal c-myc expression in mice from all transgenic lines, indicating that c-myc is a critical in vivo downstream effector of Pkd1 molecular pathways. This study not only produced an invaluable and first PKD model to evaluate molecular pathogenesis and therapies but also provides evidence that gain of function could be a pathogenetic mechanism in ADPKD.

scholarly journals Acute Kidney Injury Episodes and Chronic Kidney Disease Risk in Diabetes Mellitus

2011 ◽  
Vol 6 (11) ◽  
pp. 2567-2572 ◽  
Author(s):  
Charuhas V. Thakar ◽  
Annette Christianson ◽  
Jonathan Himmelfarb ◽  
Anthony C. Leonard
Keyword(s):  
Diabetes Mellitus ◽  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Disease Risk ◽  
Kidney Injury ◽  
Chronic Kidney Disease Risk

scholarly journals African Ancestry–Specific Alleles and Kidney Disease Risk in Hispanics/Latinos

2016 ◽  
Vol 28 (3) ◽  
pp. 915-922 ◽  
Author(s):  
Holly J. Kramer ◽  
Adrienne M. Stilp ◽  
Cathy C. Laurie ◽  
Alex P. Reiner ◽  
James Lash ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Risk ◽  
African Ancestry

scholarly journals Acute kidney injury in children hospitalized for community acquired pneumonia

2021 ◽  
Author(s):  
Pierluigi Marzuillo ◽  
Vincenza Pezzella ◽  
Stefano Guarino ◽  
Anna Di Sessa ◽  
Maria Baldascino ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Severe Pneumonia ◽  
Community Acquired Pneumonia ◽  
Normative Values ◽  
Duration Of Symptoms ◽  
Logistic Regression Models ◽  
Protein Levels ◽  
Stage 1

Abstract Background Acute kidney injury (AKI) enhances the risk of later chronic kidney disease. Significant prevalence of AKI is reported in adults with community acquired pneumonia (CAP). We investigated prevalence of and prognostic factors for AKI in children hospitalized for CAP. Methods We retrospectively collected clinical and biochemical data of 186 children (48.4% male; mean age 2.6±2.4 years) hospitalized for X-ray-confirmed CAP. AKI was defined according to Kidney Disease/Improving Global Outcomes creatinine criteria. We considered as basal serum creatinine the value estimated with Hoste (age) equation assuming basal eGFR were median age-based eGFR normative values for children ≤ 2 years of age and eGFR= 120 mL/min/1.73m2 for children > 2 years. Univariate and multivariate logistic regression models were used to explore associations with AKI. Results AKI was found in 38/186 (20.4%) patients. No patient required hemodialysis nor reached AKI stage 3, 5 (2.7%) reached AKI stage 2, and 33 (17.7%) AKI stage 1. Mean length of stay was 6.0±1.7, 6.9±2.3, and 12.2±1.5 days, for patients without AKI, stage 1 AKI, and stage 2 AKI (p < 0.001), respectively. Duration of symptoms before hospitalization (OR 1.2; 95%CI 1.09–1.43; p = 0.001), severe pneumonia (OR 11.9; 95%CI 4.3–33.3; p < 0.001), and serum C-reactive protein levels (OR 1.1; 95%CI 1.04–1.23; p = 0.004) were independent AKI predictors. Conclusions About 1/5 of children hospitalized for CAP present a generally mild AKI with a longer stay for those with more severe AKI. Attention should be paid to kidney health of children with CAP especially in presence of higher duration of symptoms before hospitalization, severe pneumonia and higher serum CRP levels. Graphical Abstract

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