Abstract
Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, after severe injury they accumulate and contribute to persistent inflammation. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making the cells vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.
Highlights
Acute kidney injury (AKI) afflicts 1.2 million hospitalized patients annually in the US; twenty to fifty percent of AKI survivors progress to chronic kidney disease (CKD), increasing their risk for dialysis-dependency, cardiovascular events, and mortality [1,2,3]
Among the damage-induced genes expressed in this dedifferentiated inflammatory proximal tubular (PT) cell state, we focused on the enrichment of Sox9 and Vcam1 (Fig. 1D, See down-regulated in this PT cell state (DA-PT) cluster, arrowheads)
To address whether the emergence of damage-associated PT cells is specific to injured kidneys (IRI) injury or appears in other cases of acute kidney injury, we investigated the co-expression of SOX9 and vascular cell adhesion molecule 1 (VCAM1) in models of toxic renal injury and obstructive renal injury, which lead to severe fibrosis
Summary
Acute kidney injury (AKI) afflicts 1.2 million hospitalized patients annually in the US; twenty to fifty percent of AKI survivors progress to chronic kidney disease (CKD), increasing their risk for dialysis-dependency, cardiovascular events, and mortality [1,2,3]. In the renal repair process, damaged PT cells adopt heterogeneous molecular states [10]. They reactivate genes normally active during renal development [11,12,13], alter their dependency on metabolic fuels [14], change their morphology, and proliferate to replenish the areas of denuded epithelium in the proximal tubule [7, 15]. The molecular pathways that govern proximal tubular heterogeneity and cell fate during failed renal repair after severe injury are poorly understood. This knowledge gap prevents the development of therapies based on underlying disease mechanisms
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