Tubular Epithelial Cell Senescence Associated Secretory Phenotype: Impact on Regeneration in Acute and Chronic Kidney Disease

• Applicant: Professor Dr. Roland Schmitt
• Subject Area: Nephrology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277609771

Acute kidney injury (AKI) is a common and serious clinical problem which is associated with a high morbidity. The incidence of AKI is steadily rising, which is largely due to an increase in the aging population. This is of particular concern because the recovery rate after AKI is significantly worse with advancing age. Older people are more likely to develop chronic renal failure and to become dialysis dependent after AKI. Several distinct age-dependent mechanisms have been identified that might underlie this problem. Among these mechanisms, Somatic Cellular Senescence (SCS) has emerged as one of the most powerful pathways. SCS is a state of irreversible cell cycle arrest in which the cell remains viable but develops altered functional and metabolic activity. This includes a specific expression pattern of secreted proteins which is referred to as the Senescence-Associated-Secretory-Phenotype (SASP). Recent studies have shown that the SASP is responsible for significant paracrine changes in the cellular microenvironment leading to a profound disruption of normal tissue homeostasis. In the kidney, no research on the role of the SASP has been conducted so far. In preliminary studies, we found that renal tubular cells develop a significantly altered secretome when SCS is induced. Co-culturing of kidney fibroblasts with senescent tubular cells caused a rapid activation into pro-fibrotic matrix producing myofibroblasts. Based on these findings we hypothesize that tubular SCS and in particular the Tubular Epithelial Cell - SASP (TEC-SASP) are important contributors to maladaptive renal repair. It is the goal of the proposed project to investigate this hypothesis using a combination of in vitro and in vivo strategies. As a proof of concept study we will investigate transgenic mice which allow for a selective elimination of senescent cells after AKI. Our hypothesis is that the clearance of SCS will ameliorate pro-aging and pro-fibrotic mechanisms and will improve kidney repair. Focussing on the cross-talk of senescent tubular cells with infiltrating leukocytes we will study the effects of TEC-SASP on macrophage polarization in AKI-damaged kidneys. Moreover, we will study novel candidate factors that were differentially regulated in a microarray study of senescent tubular cells. In particular, we will study the role of plasminogen-activating-factor-2 (PAI-2) and of Klotho using in vitro genetic overexpression or knock-down strategies for co-culture systems and mice with targeted gene deletion for in vivo analysis. Ultimately, we will correlate our data to patient renal biopsies from the local kidney transplant program. The long-term objective of our proposal will not only be a better biological understanding of SCS and SASP but also the identification of new molecular targets that could be of potential therapeutic use for improving renal outcome in acute and chronic kidney disease.

• DFG Programme: Research Grants