Inhibition of MCL-1 to eliminate senescent cells and mitigate renal fibrosis in aristolochic acid nephropathy.

Peng Gao, Schrodinger Cenatus, Nathalie Henley, Vincent Pichette, Frédérick A Mallette, Jonatan Barrera-Chimal, Casimiro Gerarduzzi

Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada. · pubmed

Paper

Abstract

The role of tubular epithelial cells (TEC) senescence in the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains debated due to the complexity of senescent cell populations and their pro-survival mechanisms. To directly assess the contribution of TEC senescence to AKI-to-CKD progression, we employed an aristolochic acid nephropathy (AAN) mouse model. Here, we demonstrated that AAI-induced DNA damage specifically drives TEC senescence during AKI-to-CKD progression. Concomitant with the emergence of senescence, immunofluorescence staining revealed the expression of anti-apoptotic proteins, including BCL-2, BCL-xL, and MCL-1, within KIM1⁺ tubules-a marker of tubular injury. To further characterize these senescent cells, we integrated this model with snRNA-Seq data and identified a distinct population of KIM1

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Research summary

The paper claims that inhibiting MCL-1 can eliminate senescent tubular epithelial cells and mitigate renal fibrosis in a model of nephropathy. This research is relevant as it addresses the role of cellular senescence in kidney disease, which is a significant aspect of aging and age-related organ decline.

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