Acute kidney injury (AKI) is a very common, life-threatening condition and associated with an enormous burden for society, both in social as well as economic terms. Patients affected by AKI are at a highly increased risk of developing not only dialysis-requiring endstage renal failure but also cardiovascular complications such as heart failure, heart attack and stroke. Being an aging-associated disease the importance of AKI has been increasing in the last decades and will become a major challenge to modern health-care systems. Unfortunately, until now a targeted approach for the prevention and treatment of AKI has not been identified.
Our research: Dr. Müller’s group approaches this problem employing the power of the model organism C. elegans exploiting the fact that longevity in this model reflects increased stress resistance in an evolutionarily conserved manner. C. elegans is the perfect tool to elucidate the molecular mechanisms underlying this increased stress resistance. Understanding these mechanisms is the essential basis to developing novel strategies for the clinical setting, that are urgently required taking into account the quickly rising incidence of AKI due to demographic changes. Interestingly, pathways involved in lifespan regulation and stress resistance such as hypoxia-inducible factor signaling also play an important role in tumorigenesis. This fact allows for the intriguing hypothesis of a tightly regulated balance between cellular stress tolerance on the one hand and tumor suppression on the other hand. Consequently, unraveling the molecular mechanisms behind this phenomenon holds the promise to allow for targeted strategies regarding not only the protection from organ damage but also anti-tumor therapy. Regarding these questions they are especially interested in the contribution of non-coding RNAs (ncRNAs) and RNA-binding proteins (RBPs). The regulatory network linking ncRNAs, RBPs and mRNAs has so far not been studied systematically regarding renal disease.
Our successes: C. elegans is one of the key model organisms to study molecular mechanisms regulating longevity and stress resistance. Consequently, a large number of the signal transduction pathways involved in these phenotypes has been identified using the nematode. Work from Dr. Müller and his team was among the first evidence showing that hypoxia-inducible factor signaling is one of these pathways linking stress resistance, longevity and tumorigenesis even closer to each other. As to non-coding RNAs in the kidney, Dr. Müller contributed to the very first microRNA expression profiles from different cell types in the kidney. Furthermore his group published work showing the importance of this RNA species to kidney development and function.
Our goals: Linking RNA biology with the power of model organisms such as C. elegans bears a huge potential to reveal novel approaches for fighting kidney disease as well as consecutive morbidity and mortality. Unraveling this potential and translating it to a clinical use is their declared aim.
Our methods / techniques: To study the regulation of lifespan as well as cellular stress resistance Dr. Müller’s group employs cell culture as well as C. elegans. These tools are complemented by mouse models of acute kidney injury involving both ischemia reperfusion and toxic damage. The role of non-coding RNAs as well as protein-RNA interactions in respect to cellular and organ(ismal) stress resistance is unraveled using RNA-protein crosslinking and ncRNA library cloning combined with deep sequencing.
Figure 1: C. elegans is the perfect model organism to study nuclear translocation of transcription factors mediating longevity and stress resistance as shown here for HLH-30 at its basal state (left panel) and after heatshock (right panel).
Figure 2: Lifespan analysis in C. elegans showing longevity mediated by loss of renal tumor supressor protein pVHL.
Figure 3: The lab employs model organisms such as C. elegans to study the molecular mechanisms underlying human kidney disease (artwork by Puneet Bharill).