Acute kidney injury (AKI) is a very frequent and challenging clinical problem, which is associated with high morbidity and mortality. Other than dialysis, there are currently no therapeutic interventions, which reliably improve survival, limit kidney injury, or speed recovery in AKI. Therefore, there is a high unmet medical need for novel pharmacological approaches to treat AKI and to prevent the transition from AKI to chronic kidney disease (CKD). In AKI, renal tubular epithelial cells (TECs) represent the major site of injury, and exhibit pronounced plasticity to adapt to stress conditions, to adopt a proliferative state and to repair damaged tubules. This stress response and repair mechanisms of TECs can restore tissue homeostasis, and AKI can therefore be reversible. However, if the epithelial stress response is insufficient or maladaptive, AKI can progress to CKD. The molecular mechanisms of the TEC stress response upon AKI are so far incompletely understood. In our preliminary work, we established a novel AKI model employing primary kidney tubular epithelial organoids (“tubuloids”) from both humans and mice. We then used this model – in combination with a mouse model of AKI and precision-cut kidney slice cultures – to test the hypothesis that glucocorticoids, which are widely used in the clinic due to their profound anti-inflammatory effects, could promote stress resistance of TECs via anti-inflammatory mechanisms. Unexpectedly, we found that activation of the glucocorticoid receptor (GR), e.g. by application of dexamethasone, promotes a maladaptive transcriptional programme in TECs to aggravate AKI. As these preliminary data indicated that GR activation might not represent an optimal AKI treatment strategy, we continued our search for more advantageous pharmacological targets. The liver X receptors (LXRs), LXRα and LXRβ, are nuclear receptors for derivatives of cholesterol, and are best-known for their role in lipid metabolism. In mouse models of kidney injury, LXR activation in macrophages has been shown to mediate beneficial anti-inflammatory effects. Intriguingly, we observed that LXRβ is also strongly expressed in TECs in humans and mice; however, the functional relevance of epithelial LXRβ in kidney injury and repair is unknown. Interestingly, our preliminary data in tubuloid and mouse models of kidney injury now indicate an important protective role of epithelial LXRβ in kidney injury. In the proposed work programme, we would therefore like to delineate the function of epithelial LXRβ in coping with tubular injury, and in promoting repair to restore tissue homeostasis after damage. Our goal is to identify the transcriptional programmes controlled by LXRβ in TECs to govern stress resistance and repair, including the dynamics of these transcriptional programmes on a single cell level. Moreover, we aim to uncover LXRβ-dependent mechanisms of immunometabolic rewiring, which are relevant to kidney injury and repair.
DFG Programme
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