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논문분류	춘계학술대회 초록집
제목	Cell Death and Inflammation in the Progression of Cystic Kidney Disease
저자	Emilia Kieckhoefer
출판정보	2026; 2026(1):
키워드	Cystic kidney diseases, cell death, necroptosis, inflammation, ciliopathies
초록	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. Conclusion: 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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