RESUMO
African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.
Assuntos
Apolipoproteínas/genética , Glomérulos Renais/metabolismo , Lipoproteínas HDL/genética , Podócitos/metabolismo , Insuficiência Renal Crônica/genética , Albuminúria/genética , Alelos , Animais , Apolipoproteína L1 , Autofagia/genética , Azotemia/genética , Western Blotting , Endocitose/genética , Endossomos/metabolismo , Imunofluorescência , Predisposição Genética para Doença , Variação Genética , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Células HEK293 , Células HeLa , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Podócitos/ultraestrutura , Insuficiência Renal Crônica/patologiaRESUMO
Renal involvement is the major cause of morbidity and mortality in lupus. Besides autoantibodies, intrinsic renal factors may contribute to the susceptibility to lupus nephritis. To determine how different mouse strains that develop spontaneous lupus fare in their susceptibility to immune mediated nephritis, mice from six lupus-prone strains and two non-lupus control strains (B6 and BALB/c) were challenged with rabbit anti-GBM sera. Among the strains tested, NZM2410 (or NZM) mice developed severe glomerulonephritis (GN), whereas BXSB and B6.lpr, NZB mice were relatively resistant to anti-GBM disease, as were the BALB/c controls. BWF1 and B6.Yaa mice exhibited intermediate degrees of GN that was comparable to the B6 controls. The severity of the renal disease in these strains did not appear to be related to the degree of the systemic immune response to the administered rabbit Ig. In addition, cytokine profiling demonstrated differential urinary excretion of several molecules in the NZM mice, compared with the controls. Together with our previous reports, our studies demonstrate that lupus-prone strains vary in their susceptibility to immune mediated nephritis, despite similar levels of circulating autoantibodies and comparable degrees of immune complex deposition in the kidneys.
