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APOL1-G0 protects podocytes in a mouse model of HIV-associated nephropathy.

ABSTRACT: 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. The podocyte function of APOL1-G0 versus APOL1-G2 in the setting of a known disease stressor was assessed using transgenic mouse models. Transgene expression, 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. Mice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that co-expressed 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 co-expressing 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. APOL1-G0 expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This was absent with APOL1-G2 expression, suggesting APOL1-G2 may have lost this protective function.

SUBMITTER: Bruggeman LA

PROVIDER: S-EPMC6818796 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ARB protects podocytes from HIV-1 nephropathy independently of podocyte AT1.

Project description:BackgroundAngiotensin I-converting enzyme inhibitors and angiotensin receptor blockers protect podocytes more effectively than other anti-hypertensive drugs. Transgenic rats overexpressing angiotensin II Type 1 (AT1) receptor selectively in podocytes have been shown to develop glomerulosclerosis. The prevailing hypothesis is that angiotensin II has a capacity of directly acting on the AT1 receptor of podocytes to induce injury. We therefore investigated the mechanism of reno-protective effect of AT1 receptor in a mouse model of HIV-1 nephropathy.MethodsWe generated transgenic mice carrying the HIV-1 gene (control/HIV-1) or both HIV-1 gene and podocyte-selectively nullified AT1 gene (AT1KO/HIV-1). In these mice, we measured urinary protein or albumin excretion and performed histological analysis.ResultsAt 8 months of age, AT1KO/HIV-1 (n = 13) and control/HIV-1 (n = 15) mice were statistically indistinguishable with respect to urinary albumin/creatinine ratio (median 2.5 versus 9.1 mg/mg), glomerulosclerosis (median 0.63 versus 0.45 on 0-4 scale) and downregulation of nephrin (median 6.90 versus 7.02 on 0-8 scale). In contrast to the observed lack of effect of podocyte-specific AT1KO, systemic AT1 inhibition with AT1 blocker (ARB) significantly attenuated proteinuria and glomerulosclerosis in HIV-1 mice.ConclusionThese results indicate that the protective effect of ARB is mediated through its receptors on cells other than podocytes, such as efferent arteriolar smooth muscle cells.

| S-EPMC3408939 | biostudies-literature

APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy.

Project description:Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P = 0.01) and faster progression to ESRD (P < 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIV-infected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.

| S-EPMC3231787 | biostudies-literature

An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy.

Project description:Modern antiretroviral therapies (ART) have decreased the prevalence of HIV-associated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with HIVAN all over the world. Furthermore, once HIVAN is established in children, it is difficult to revert its long-term progression, and we need better animal models of childhood HIVAN to test new treatments. To define whether the HIV-1 trans-activator (Tat) gene precipitates HIVAN in young mice, and to develop an inducible mouse model of childhood HIVAN, an HIV-Tat gene cloned from a child with HIVAN was used to generate recombinant adenoviral vectors (rAd-Tat). rAd-Tat and LacZ control vectors (2×109) were expressed in the kidney of newborn wild-type and HIV-transgenic (Tg26) FVB/N mice without significant proteinuria (n=5; 8 per group). Mice were sacrificed 7 and 35 days later to assess their renal outcome, the expression of HIV-genes and growth factors, and markers of cell growth and differentiation by RT-qPCR, immunohistochemistry and/or western blots. HIV-Tat induced the expression of HIV-1 genes and heparin-binding growth factors in the kidney of HIV-Tg26 mice, and precipitated HIVAN in the first month of life. No significant renal changes were detected in wild-type mice infected with rAd-Tat vectors, suggesting that HIV-Tat alone does not induce renal disease. This new mouse model of childhood HIVAN highlights the critical role that HIV-Tat plays in the pathogenesis of HIVAN, and could be used to study the pathogenesis and treatment of HIVAN in children and adolescents.

| S-EPMC7648609 | biostudies-literature

Apolipoprotein L1 (APOL1) Variants (Vs) a possible link between Heroin-associated Nephropathy (HAN) and HIV-associated Nephropathy (HIVAN).

Project description:In 1970s, Heroin-associated Nephropathy (HAN), one form of focal and segmental glomerulosclerosis (FSGS), was a predominant cause of End-stage Kidney Disease (ESKD) in African-Americans (AAs). In 1980s, with the surge of Acquired Immune Deficiency Syndrome (AIDS) in AAs, HAN more or less disappeared, and the incidence of Human Immunodeficiency Virus associated Nephropathy (HIVAN) markedly increased. Recent studies in AAs have identified APOL1 variants (Vs) as a major risk factor for the development and progression of non-diabetic kidney diseases including idiopathic FSGS and hypertension-attributed nephrosclerosis. These observations have also offered partial insights into the mechanisms of development, and higher rate of occurrence of both HAN and HIVAN in AAs. AAs with APOL1Vs develop idiopathic FSGS at four-fold higher rate compared to European Americans (EAs). Similarly, HIV infected AAs with APOL1Vs (if not on antiviral therapy), risk a 50% (10-fold greater) chance of developing HIVAN. It has been suggested that APOL1Vs expression may render podocytes more vulnerable to various types of injury: bacterial, viral, and others. However, in addition to genetic variants, additional factors such as persistence of a second hit may determine the nature and severity of glomerular disease. In patients with HAN, heroin or contaminants may have been the offending second insult(s) which caused renal disease in susceptible AA patients. In the 80's, since heroin-induced second hit was neither consistent nor sustained (depending on drug availability in the street), the disease was masked or replaced HIV infected patients (especially in untreated subjects), by an overwhelming second hit by the virus which was both intense as well as persistent. It appears that APOL1Vs may be one of the links between the disappearance of HAN and emergence of HIVAN in AA patients.

| S-EPMC4460807 | biostudies-literature

APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans.

Project description:APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a South-African black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naïve South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa.

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Vitamin D receptor signaling in podocytes protects against diabetic nephropathy.

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C3a receptor blockade protects podocytes from injury in diabetic nephropathy.

Project description:Renal activation of the complement system has been described in patients with diabetic nephropathy (DN), although its pathological relevance is still ill-defined. Here, we studied whether glomerular C3a, generated by uncontrolled complement activation, promotes podocyte damage, leading to proteinuria and renal injury in mice with type 2 diabetes. BTBR ob/ob mice exhibited podocyte loss, albuminuria, and glomerular injury accompanied by C3 deposits and increased C3a and C3a receptor (C3aR) levels. Decreased glomerular nephrin and α-actinin4 expression, coupled with integrin-linked kinase induction, were also observed. Treatment of DN mice with a C3aR antagonist enhanced podocyte density and preserved their phenotype, limiting proteinuria and glomerular injury. Mechanistically, ultrastructural and functional mitochondrial alterations, accompanied by downregulation of antioxidant superoxide dismutase 2 (SOD2) and increased protein oxidation, occurred in podocytes and were normalized by C3aR blockade. In cultured podocytes, C3a induced cAMP-dependent mitochondrial fragmentation. Alterations of mitochondrial membrane potential, SOD2 expression, and energetic metabolism were also found in response to C3a. Notably, C3a-induced podocyte motility was inhibited by SS-31, a peptide with mitochondrial protective effects. These data indicate that C3a blockade represents a potentially novel therapeutic strategy in DN for preserving podocyte integrity through the maintenance of mitochondrial functions.

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Gene-gene interactions in APOL1-associated nephropathy.

Project description:Two APOL1 nephropathy variants confer substantial risk for non-diabetic end-stage kidney disease (ESKD) in African Americans (AAs). Since not all genetically high-risk individuals develop ESKD, modifying factors likely contribute. Forty-two potentially interactive single nucleotide polymorphisms (SNPs) from a genome-wide association study in non-diabetic ESKD were tested for interaction with APOL1 to identify genes modifying risk for non-diabetic nephropathy.SNPs were examined in an expanded sample of 1367 AA non-diabetic ESKD cases and 1504 AA non-nephropathy controls, with validation in an independent family-based cohort containing 608 first-degree relatives of index cases with non-diabetic ESKD. Logistic regression and mixed models were fitted to test for interaction effects with APOL1 on ESKD, estimated kidney function and albuminuria.Among ESKD samples, 14 of 42 SNPs demonstrated suggestive APOL1 interaction with P-values <0.05. After Bonferroni correction, significant interactions with APOL1 were seen with SNPs in podocin (rs16854341; NPHS2, P = 8.0 × 10(-4)), in SDCCAG8 (rs2802723; P = 5.0 × 10(-4)) and near BMP4 (rs8014363; P = 1.0 × 10(-3)); with trends for ENOX1 (rs9533534; P = 2.2 × 10(-3)) and near TRIB1 (rs4457349; P = 5.7 × 10(-3)). The minor allele in NPHS2 markedly changed the APOL1-ESKD association odds ratio (OR) from 7.03 to 1.76 (?50% reduction in effect per copy of the minor allele), rs2802723 changed the OR from 5.1 to 10.5, and rs8014363 increased the OR from 4.8 to 9.5. NPHS2 (P = 0.05) and SDCCAG8 (P = 0.03) SNPs demonstrated APOL1 interaction with albuminuria in independent family-based samples.Variants in NPHS2, SDCCAG8 and near BMP4 appear to interact with APOL1 to modulate the risk for non-diabetic ESKD in AAs.

| S-EPMC3938297 | biostudies-literature

APOL1-G0 or APOL1-G2 Transgenic Models Develop Preeclampsia but Not Kidney Disease.

Project description:APOL1 risk variants are associated with kidney disease in blacks, but the mechanisms of renal injury associated with APOL1 risk variants are unknown. Because APOL1 is unique to humans and some primates, we created transgenic (Tg) mice using the promoter of nephrin-encoding Nphs1 to express the APOL1 reference sequence (G0) or the G2 risk variant in podocytes, establishing Tg lines with a spectrum of APOL1 expression levels. Podocytes from Tg-G0 and Tg-G2 mice did not undergo necrosis, apoptosis, or autophagic cell death in vivo, even in lines with highly expressed transgenes. Further, Tg-G0 and Tg-G2 mice did not develop kidney pathology, proteinuria, or azotemia as of 300 days of age. However, by 200 days of age, Tg-G2 mice had significantly lower podocyte density than age-matched WT and Tg-G0 mice had, a difference that was not evident at weaning. Notably, a pregnancy-associated phenotype that encompassed eclampsia, preeclampsia, fetal/neonatal deaths, and small litter sizes occurred in some Tg-G0 mice and more severely in Tg-G2 mice. Similar to human placenta, placentas of Tg mice expressed APOL1. Overall, these results suggest podocyte depletion could predispose individuals with APOL1 risk genotypes to kidney disease in response to a second stressor, and add to other published evidence associating APOL1 expression with preeclampsia.

| S-EPMC5118487 | biostudies-literature