Regulation of p21-induced tubular senescence and impaired renal regeneration in the context of diabetic kidney disease: the role of coagulation factor FXII

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An unsolved medical problem of diabetic kidney disease (DKD) is the lack of renal recovery despite therapy (the so-called "hyperglycaemic memory"). Renal cell senescence and epigenetically fixed gene dysregulation associated with sterile inflammation are thought to contribute to hyperglycaemic memory. This assumption is supported, among other things, by our own data, demonstrating a persistent induction of the cell cycle regulator and senescence-associated gene p21 despite improved metabolic control in people with diabetes and diabetic mice. Persistent p21 expression was epigenetically regulated, associated with tubular senescence and sterile inflammation, but could be reversed by DNMT1 induction. Yet, it remains unknown whether p21 induction is sufficient to induce tubular senescence and the associated sterile inflammation, what the cellular consequences of tubular senescence are, whether the associated profile of inflammatory cells contributes to failed disease resolution, or whether the elimination of senescent cells positively affects the course of DKD and/or the regeneration potential of the kidney. The mechanism leading to tubular senescence are also unclear. In further unpublished data, we were able to show that the zymogen coagulation factor XII (FXII) is increased in urine and in tubular cells in DKD. Additionally, FXII contributes to the development of experimental DKD, associated senescence and sterile inflammation. In vitro experiments suggest that the zymogen FXII induces these effects through a receptor-mediated mechanism (via uPAR). However, it is unclear what pathological relevance tubular FXII expression has (auto- or paracrine FXII effect?), which additional receptors convey the FXII-mediated effects (possibly integrins), and whether FXII is a therapeutic target in DKD. We postulate that increased tubular FXII expression induces (auto or paracrine) p21-associated tubular senescence, contributing to tubular dysfunction and sterile inflammation. These mechanisms inhibit renal repair mechanisms in DKD. In order to test this hypothesis, we intend to study the following aims: 1. Characterization of the pathogenetic relevance of p21-associated tubular senescence for the perpetuation of DKD; 2. Characterization of the mechanism by which FXII induces tubular senescence. State-of-the-art approaches will be used to address these aims (e.g. snRNAseq, snATACseq, new mouse models, e.g. in vivo cell tracing or targeted elimination of senescent cells). These studies will provide new and mechanistic insights into the importance of tubular senescence for the perpetuation of DKD and will investigate a novel role of the zymogen FXII in DKD.