We have discovered a novel "ischemic-AKI" MAVS-pathway that exacerbates ischemic acute kidney injury (AKI). Reactive oxygen species (ROS) produced during ischemic AKI activate MAVS (Mitochondria Anti-Viral Signaling protein), MAVS activates IRF1 (interferon regulatory factor 1), and IRF1 stimulates the production of maladaptive ?-IFNs (alpha interferons). Ischemia/ reperfusion ? ROS ? MAVS activation ? activation of IRF1 gene ? ?-IFN production ? IFN?? receptor ligation ? renal injury. The above pathway is supported by our in vivo and in vitro data. Transgenic knockout of MAVS, IRF1, or the IFN receptor confirm this sequence of events during ischemic AKI in vivo. siRNA knockdown of MAVS, or IRF1 confirm the sequence in ROS-stimulated renal tubular epithelia in vitro. MAVS, and ?-IFNs are molecules that, previous to our work, were only known to participate in anti-viral responses. Whereas the "anti-viral" MAVS-pathways are triggered by cytoplasmic viral nucleic acids, our "ischemic-AKI" MAVS-pathway is triggered by ROS generated during ischemic AKI. We also propose novel roles for mitochondria and peroxisomes in ischemic AKI (see Aim I). We found that a critical intermediate step in the "ischemic-AKI" MAVS-pathway is activation of the IRF1 gene. IRF1 then activates ?-IFNs. In contrast to its importance in ischemic AKI, IRF1 is not a critical intermediate in the host defense against most viral infections. Therefore, we focus this proposal on understanding the activation of IRF1. This understanding will lead to new therapies that would interdict the maladaptive effects of the "ischemic-AKI" MAVS-pathway by inhibiting IRF1 gene activation, without a major negative impact on anti-viral responses most of which are IRF1 independent.
Aim I : Does ischemic-AKI activate the IRF1 gene, and downstream ?-IFNs, via the "peroxisomal" or "mitochondrial" MAVS-pathways? The key regulatory protein in our novel "ischemic-AKI" MAVS-pathway is MAVS. MAVS has a C-terminal transmembrane motif that embeds it into peroxisomal and mitochondrial membranes. In response to viruses, the peroxisomal versus mitochondrial MAVS activate different genes. The former is a minor component during most viral infections. The viral peroxisomal, but not the mitochondrial, MAVS pathway shares the use of the transcription factor IRF1 with the "ischemic-AKI" MAVS-pathway. We will determine if the "ischemic-AKI" MAVS-pathway uses peroxisomal MAVS. We will determine if specifically activating or inhibiting the mitochondrial versus peroxisomal pathways inhibits IRF1 activation.
Aim II : Does a unique combination of transcription factors activate IRF1 in the "ischemic-AKI" MAVS- pathway? We will test the hypothesis that the "ischemic-AKI" and "anti-viral" MAVS-pathway activate different transcription factors. This would explain why the former activates IRF1, while the latter does not.
Ischemic acute kidney injury has a high prevalence, immediate mortality, and leads to long term progressive chronic kidney disease. No treatment of the underlying causes of acute kidney injury is now available. Our research aims to understand the underlying causes and may thus result in effective treatment.
|Lu, Christopher Y (2014) ?-Lapachone ameliorates murine cisplatin nephrotoxicity: NAD?, NQO1, and SIRT1 at the crossroads of metabolism, injury, and inflammation. Kidney Int 85:496-8|