APOL1Renal-Risk Variants Induce Mitochondrial Dysfunction

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Mitochondrial reactive oxygen species regulate transforming growth factor-β signaling.

Carol Feghali-Bostwick, James Eisenbart, N Chandel … (2013)

TGF-β signaling is required for normal tissue repair; however, excessive TGF-β signaling can lead to robust profibrotic gene expression in fibroblasts, resulting in tissue fibrosis. TGF-β binds to cell-surface receptors, resulting in the phosphorylation of the Smad family of transcription factors to initiate gene expression. TGF-β also initiates Smad-independent pathways, which augment gene expression. Here, we report that mitochondrial reactive oxygen species (ROS) generated at complex III are required for TGF-β-induced gene expression in primary normal human lung fibroblasts. TGF-β-induced ROS could be detected in both the mitochondrial matrix and cytosol. Mitochondrially targeted antioxidants markedly attenuated TGF-β-induced gene expression without affecting Smad phosphorylation or nuclear translocation. Genetically disrupting mitochondrial complex III-generated ROS production attenuated TGF-β-induced profibrotic gene expression. Furthermore, inhibiting mitochondrial ROS generation attenuated NOX4 (NADPH oxidase 4) expression, which is required for TGF-β induced myofibroblast differentiation. Lung fibroblasts from patients with pulmonary fibrosis generated more mitochondrial ROS than normal human lung fibroblasts, and mitochondrially targeted antioxidants attenuated profibrotic gene expression in both normal and fibrotic lung fibroblasts. Collectively, our results indicate that mitochondrial ROS are essential for normal TGF-β-mediated gene expression and that targeting mitochondrial ROS might be beneficial in diseases associated with excessive fibrosis.

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Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1

Brendan Nichols, Prachi Jog, Jessica L. Lee … (2014)

Apolipoprotein L1 (APOL1) risk variants greatly elevate the risk of kidney disease in African Americans. Here we report a cohort of patients who developed collapsing focal segmental glomerulosclerosis while receiving therapeutic interferon, all of whom carried the APOL1 high-risk genotype. This finding raised the possibility that interferons and the molecular pattern recognition receptors that stimulate interferon production may contribute to APOL1-associated kidney disease. In cell culture, interferons and toll-like receptor agonists increased APOL1 expression by up to 200-fold, in some cases with the appearance of transcripts not detected under basal conditions. PolyI:C, a double-stranded RNA TLR3 agonist, increased APOL1 expression by upregulating interferons directly or through an interferon-independent, IRF-3 dependent pathway. Using pharmacological inhibitors, shRNA knockdown, and chromatin immunoprecipitation, we found that the interferon-independent TLR3 pathway relied on signaling through TBK1, NF-kB, and Jak kinases, and on binding of IRF1, IRF2, and STAT2 at the APOL1 transcription start site. We also demonstrate that overexpression of the APOL1 risk variants is more injurious to cells than overexpression of the wild-type APOL1 protein. Our study illustrates that anti-viral pathways may be an important inducer of kidney disease in individuals with the APOL1 high-risk genotype and identifies potential targets for prevention or treatment.

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TGF-beta in renal injury and disease.

Erwin P Bottinger (2007)

Chronic progressive kidney diseases typically are characterized by loss of differentiated epithelial cells and activation of mesenchymal cell populations leading to renal fibrosis in response to a broad range of diverse renal injuries. Recent evidence has indicated that epithelial microinjury leads to unbalanced epithelial-mesenchymal communication to initiate the fibrotic response. Transforming growth factors beta constitute a large family of cytokines that control key cellular responses in development and tissue repair. Activation of autocrine and paracrine transforming growth factor-beta signaling cascades in the context of epithelial microinjuries initiate a variety of cell type-dependent signaling and activity profiles, including epithelial apoptosis and epithelial-to-mesenchymal transition, that trigger fibrogenic foci and initiate progressive fibrogenesis in chronic renal injury.