Riboregulation - the moonlighting function of the aldolase family in acute kidney injury and nephroprotection

• Applicant: Michael Ignarski, Ph.D.
• Subject Area: Nephrology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 522972244

Acute kidney injury (AKI) is a worldwide public health problem associated with a high risk of mortality, increased length of hospitalization and development of chronic kidney disease. In the past decades the incidence of AKI increased progressively, but so far no effective interventions have been developed to improve the outcomes of AKI. To counteract this development with novel diagnostic tools and targeted therapies a better understanding of the underlying pathophysiology of AKI is required. One of the most promising approaches to attenuate or prevent AKI entirely, is to increase the stress resistance of the kidney prior to a causative treatment (e.g. surgery). The so-called preconditioning strategies, achieved by the exposure of the organism to stress conditions like dietary restriction or hypoxia, have been applied to a wide range of model organisms and have recently entered clinical trials. Although the effects of preconditioning have been studied for almost a decade, the molecular basis of these effects are still under investigation. In our previous studies on mouse models of AKI and preconditioning we applied transcriptomic and proteomic analyses to identify proteins differentially regulated by AKI and preconditioning. For several reasons the proteins the Aldolase family, highly conserved enzymes of the glycolytic pathway, caught our attention. (1) AKI is often linked to metabolic pathways and their reprogramming. (2) Many, well characterized glycolytic enzymes like the aldolases bind RNA without carrying classical RNA-binding domains. (3) Recent studies including work from our lab discovered changes in protein/RNA-binding upon exposure to hypoxia. In the project at hand, we will follow up on our observation that aldolases interact with RNA and that this interaction is modulated in hypoxic conditions. We will identify the RNA-binding regions and characterize the RNAs bound by aldolases. Further, we will analyze the riboregulatory effects of these interactions on the enzymatic activity of aldolases and their impact on the glycolytic pathway. Finally, linking our findings on aldolase riboregulation with mouse models of AKI and protective preconditioning strategies, we will unveil the role of riboregulation in metabolic pathways and AKI. We expect that this study will open a new entry point pharmacological interventions with aldolases as a potential therapeutical target for kidney disease.

• DFG Programme: Research Grants