Portal de Periódicos da CAPES

A glomerular transcriptomic landscape of apolipoprotein L1 in Black patients with focal segmental glomerulosclerosis

2021; Elsevier BV; Volume: 102; Issue: 1 Linguagem: Inglês

10.1016/j.kint.2021.10.041

1523-1755

Michelle Mcnulty, Damian Fermin, Felix Eichinger, Dongkeun Jang, Matthias Kretzler, Noël P. Burtt, Martin R. Pollak, Jason Flannick, Astrid Weins, David J. Friedman, Matthew G. Sampson, Katherine M. Dell, John R. Sedor, M. Schachere, Jacob D. Negrey, Kevin V. Lemley, B. Silesky, Tarak Srivastava, Alfred J. Garrett, Christine B. Sethna, K. Laurent, Pietro A. Canetta, Akshyaya Pradhan, Laurence Greenbaum, C. Wang, Chunsheng Kang, Sharon G. Adler, Janine LaPage, Ambarish M. Athavale, M. Itteera, Meredith A. Atkinson, T. Dell, Fernando C. Fervenza, Marie C. Hogan, John C. Lieske, Vladimir Chernitskiy, Frederick J. Kaskel, Michael D. Ross, P. Flynn, Jeffrey B. Kopp, J. Thomas Blake, Howard Trachtman, Olga Zhdanova, Frank Modersitzki, Sandro Vento, Richard A. Lafayette, K. Mehta, Crystal A. Gadegbeku, S. Quinn-Boyle, Michelle Hladunewich, Heather N. Reich, P. Ling, Martin Romano, Alessia Fornoni, Carlos Bidot, Matthias Kretzler, Debbie S. Gipson, Amanda Williams, Catherine Klida, Vimal K. Derebail, Keisha L. Gibson, E. Cole, J. Ormond-Foster, Lawrence B. Holzman, Kevin Meyers, K. Kallem, Andrea Swenson, Kamal Sambandam, Z. Wang, M. Rogers, A. Jefferson, Sangeeta Hingorani, Katherine R. Tuttle, Mark‐Anthony Bray, Emily Pao, Ann Cooper, J.J. Lin, Stefanie Baker, Matthias Kretzler, L. Barisoni, J. Bixler, Hailey Desmond, Sean R. Eddy, Damian Fermin, Crystal A. Gadegbeku, Brenda W. Gillespie, Debbie S. Gipson, Lawrence B. Holzman, Vivian Kurtz, Maria Larkina, S. Li, S. Li, Chrysta Lienczewski, Jie Liu, T. Mainieri, Laura Mariani, Matthew G. Sampson, John R. Sedor, Abigail R. Smith, Amanda Williams, Jarcy Zee, Carmen Avila‐Casado, Serena M. Bagnasco, Joseph P. Gaut, Stephen M. Hewitt, Jeff Hodgin, Kevin V. Lemley, Laura Mariani, Matthew Palmer, Avi Z. Rosenberg, Virginie Royal, David B. Thomas, Jarcy Zee, Laura Barisoni, Cynthia C. Nast, Katherine M. Dell, John R. Sedor, M. Schachere, Jacob D. Negrey, Kevin V. Lemley, B. Silesky, Tarak Srivastava, Alfred J. Garrett, Christine B. Sethna, K. Laurent, Pietro A. Canetta, Akshyaya Pradhan, Laurence Greenbaum, C. Wang, Chunsheng Kang, Sharon G. Adler, Janine LaPage, Ambarish M. Athavale, M. Itteera, Meredith A. Atkinson, T. Dell, Fernando C. Fervenza, Marie C. Hogan, John C. Lieske, Vladimir Chernitskiy, Frederick J. Kaskel, Michael D. Ross, P. Flynn, Jeffrey B. Kopp, J. Thomas Blake, Howard Trachtman, Olga Zhdanova, Frank Modersitzki, Sandro Vento, Richard A. Lafayette, K. Mehta, Crystal A. Gadegbeku, S. Quinn-Boyle, Michelle Hladunewich, Heather N. Reich, P. Ling, Martin Romano, Alessia Fornoni, Carlos Bidot, Matthias Kretzler, Debbie S. Gipson, Amanda Williams, Catherine Klida, Vimal K. Derebail, Keisha L. Gibson, E. Cole, J. Ormond-Foster, Lawrence B. Holzman, Kevin Meyers, K. Kallem, Andrea Swenson, Kamal Sambandam, Z. Wang, M. Rogers, A. Jefferson, Sangeeta Hingorani, Katherine R. Tuttle, Mark‐Anthony Bray, Emily Pao, Ann Cooper, J.J. Lin, Stefanie Baker, Matthias Kretzler, L. Barisoni, J. Bixler, Hailey Desmond, Sean R. Eddy, Damian Fermin, Crystal A. Gadegbeku, Brenda W. Gillespie, Debbie S. Gipson, Lawrence B. Holzman, Vivian Kurtz, Maria Larkina, S. Li, S. Li, Chrysta Lienczewski, Jie Liu, T. Mainieri, Laura Mariani, Matthew G. Sampson, John R. Sedor, Abigail R. Smith, Amanda Williams, Jarcy Zee, Carmen Avila‐Casado, Serena M. Bagnasco, Joseph P. Gaut, Stephen M. Hewitt, Jeff Hodgin, Kevin V. Lemley, Laura Mariani, Matthew Palmer, Avi Z. Rosenberg, Virginie Royal, David B. Thomas, Jarcy Zee, Laura Barisoni, Cynthia C. Nast,

Chronic Kidney Disease and Diabetes

Apolipoprotein L1 (APOL1)-associated focal segmental glomerulosclerosis (FSGS) is the dominant form of FSGS in Black individuals. There are no targeted therapies for this condition, in part because the molecular mechanisms underlying APOL1's pathogenic contribution to FSGS are incompletely understood. Studying the transcriptomic landscape of APOL1 FSGS in patient kidneys is an important way to discover genes and molecular behaviors that are unique or most relevant to the human disease. With the hypothesis that the pathology driven by the high-risk APOL1 genotype is reflected in alteration of gene expression across the glomerular transcriptome, we compared expression and co-expression profiles of 15,703 genes in 16 Black patients with FSGS at high-risk vs 14 Black patients with a low-risk APOL1 genotype. Expression data from APOL1-inducible HEK293 cells and normal human glomeruli were used to pursue genes and molecular pathways uncovered in these studies. We discovered increased expression of APOL1 and nine other significant differentially expressed genes in high-risk patients. This included stanniocalcin, which has a role in mitochondrial and calcium-related processes along with differential correlations between high- and low-risk APOL1 and metabolism pathway genes. There were similar correlations with extracellular matrix- and immune-related genes, but significant loss of co-expression of mitochondrial genes in high-risk FSGS, and an NF-κB-down regulating gene, NKIRAS1, as the most significant hub gene with strong differential correlations with NDUF family (mitochondrial respiratory genes) and immune-related (JAK-STAT) genes. Thus, differences in mitochondrial gene regulation appear to underlie many differences observed between high- and low-risk Black patients with FSGS. Apolipoprotein L1 (APOL1)-associated focal segmental glomerulosclerosis (FSGS) is the dominant form of FSGS in Black individuals. There are no targeted therapies for this condition, in part because the molecular mechanisms underlying APOL1's pathogenic contribution to FSGS are incompletely understood. Studying the transcriptomic landscape of APOL1 FSGS in patient kidneys is an important way to discover genes and molecular behaviors that are unique or most relevant to the human disease. With the hypothesis that the pathology driven by the high-risk APOL1 genotype is reflected in alteration of gene expression across the glomerular transcriptome, we compared expression and co-expression profiles of 15,703 genes in 16 Black patients with FSGS at high-risk vs 14 Black patients with a low-risk APOL1 genotype. Expression data from APOL1-inducible HEK293 cells and normal human glomeruli were used to pursue genes and molecular pathways uncovered in these studies. We discovered increased expression of APOL1 and nine other significant differentially expressed genes in high-risk patients. This included stanniocalcin, which has a role in mitochondrial and calcium-related processes along with differential correlations between high- and low-risk APOL1 and metabolism pathway genes. There were similar correlations with extracellular matrix- and immune-related genes, but significant loss of co-expression of mitochondrial genes in high-risk FSGS, and an NF-κB-down regulating gene, NKIRAS1, as the most significant hub gene with strong differential correlations with NDUF family (mitochondrial respiratory genes) and immune-related (JAK-STAT) genes. Thus, differences in mitochondrial gene regulation appear to underlie many differences observed between high- and low-risk Black patients with FSGS. Impact of APOL1 kidney risk variants on glomerular transcriptomesKidney InternationalVol. 102Issue 1PreviewMcNulty and colleagues describe the glomerular transcriptional landscape of subjects with APOL1 (the gene encoding apolipoprotein L1)–associated kidney disease, using bulk RNA sequencing. They found the following: APOL1 gene expression was higher in individuals with APOL1 high-risk genetic status; in glomeruli, STC1, encoding stanniocalcin, was the most upregulated gene, and CCL18, encoding C-C motif chemokine ligand 18, was the most downregulated gene; and nuclear factor kappa BNF-κB inhibitor-interacting Ras-like 1 (NKIRAS1) is the strongest hub gene. Full-Text PDF