Abstract Type : Oral presentation
Abstract Submission No.: A-0334
Abstract Topic : Basic Research

Cell Death and Inflammation in the Progression of Cystic Kidney Disease

Emilia Kieckhoefer¹, Lena Ebert¹, Claudio Sierra Gonzales¹, Julia Guenzler¹, Hyein Paeng¹, Thomas Benzing², Bernhard Schermer¹
¹Department of Department II of Internal Medicine and Center for Molecular Medicine Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany, Germany
²Department of Department II of Internal Medicine, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany, Germany

Objectives : Cystic kidney diseases are a major global cause of end-stage renal disease and the need for kidney transplantation, and belong to the spectrum of hereditary renal ciliopathies. Although substantial work has established a key role for primary cilia in cystic kidney disease, the mechanisms underlying cyst expansion, fibrosis, and progressive loss of renal function in polycystic kidney diseases (PKDs) remain poorly defined. In acute kidney injury, regulated cell death (RCD) - particularly ferroptosis and necroptosis - has emerged as an important driver of tissue damage. By contrast, systematic studies interrogating RCD pathways and their upstream triggers in chronic PKD progression are limited, and the key factors driving renal phenotypic deterioration remain insufficiently characterized.
Methods : Using a PKD mouse model that develops early kidney tubular dilatation, inflammation, and severe cysts accompanied by fibrosis at 12 weeks of age, we were able to unravel an important role for RCD in this process. Renal single-nucleus RNA sequencing from postnatal day 4 to 12 weeks discovered cell-type-specific programs in which injury-associated cell death and proliferative expansion are dynamically balanced. Interestingly, the immune profiling of the kidney via FACS revealed a distinct separation between the genotypes. To incorporate these findings into disease progression, we additionally deleted RIPK3, a central kinase in the necroptosis pathway, in this PKD model.
Results : This genetic suppression of necroptosis ameliorated the cystic phenotype and improved kidney function. Moreover, we further confirm the role of necroptosis in PKD, as the knockout of the necroptosis effector Mlkl conferred comparable protection.
Conclusions : Together, these data identify necroptosis as a driver of progressive cystic kidney disease and establish regulated cell death pathways as tractable therapeutic targets to preserve tubular integrity and renal function.

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