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

TL;DR

This study shows that inhibiting MCL-1 during early kidney injury can reduce cell aging and prevent chronic kidney disease progression.

Contribution

The study identifies MCL-1 as a critical target for eliminating senescent tubular cells in aristolochic acid-induced kidney disease.

Findings

Aristolochic acid-induced DNA damage leads to senescence in tubular epithelial cells during AKI-to-CKD progression.

UMI-77, an MCL-1 inhibitor, effectively reduces senescence and fibrosis when administered early in kidney injury.

Senescent cells rely on specific anti-apoptotic proteins like MCL-1, BCL-2, and BCL-xL for survival.

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+ senescent TEC exhibiting resistance to apoptosis through upregulation of pro-survival proteins such as MCL-1, BCL-2, and BCL-xL. To evaluate the therapeutic potential of targeting these pathways, we treated AAN mice with the MCL-1-specific inhibitor UMI-77 and the senolytic ABT-263 (targeting BCL-2/BCL-xL) during both the acute and late phases. Interestingly, only UMI-77 administration during the acute phase effectively reduced tubular senescence and mitigated fibrosis. In contrast, late-phase treatment had only marginal benefits. Notably, ABT-263 failed to eliminate senescent cells and instead exacerbated fibrosis, suggesting that while senescent TEC relies on pro-survival mechanisms to evade apoptosis, their dependency on specific anti-apoptotic proteins varies. Our study provides a high-resolution molecular framework for understanding TEC senescence and identifies MCL-1 inhibition as a precise and effective therapeutic strategy to prevent AKI-to-CKD progression, with early intervention being critical for therapeutic success.

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