Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair

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.

Urinary single-cell sequencing captures intrarenal injury and repair processes in human acute kidney injury

“…The occurrence of multiple injury related TEC subsets with inflammatory, fibrotic and regenerative traits motivated us to ask whether our urinary data of human AKI are in accordance with recent findings in mouse AKI models describing “maladaptive” (6) or “failed-repair” (5, 9) TEC, which are suspected to drive fibrosis post AKI. We downloaded the mouse ischemia reperfusion injury dataset by Kirita et al (5), who initially described these cell states, and reconstructed the investigated PT clusters showing the emergence of injured, repairing and “failed repair” out of healthy PT cells after ischemia-reperfusion injury (Fig.…”

“…The Humphreys group first described a “failed-repair” subset in mouse AKI (5), characterized by downregulation of differentiation markers of PT cells, expression of VCAM1 and persistence after AKI. These cells have since been reported in several other mouse models for AKI, indicating an inflammatory signature, which may fuel progression to CKD (50) as well as a potential recovery of these cells governed by ferroptotic stress (9).…”

“…Our current understanding of TEC injury reaction assumes a dedifferentiation and redifferentiation after successful repair, which has been demonstrated for PT cells in several mouse models (5,8,9) and cells in human AKI biopsies have been reported to mirror this process (8). A central question is how this repair takes place and why it can fail.…”

“…Transcriptomic analyses in mouse AKI models on the single-cell level have rapidly enhanced and transformed our understanding of injured and recovering TEC states (5,6,(8)(9)(10).…”

“…Transcriptomic analyses in mouse AKI models on the single-cell level have rapidly enhanced and transformed our understanding of injured and recovering TEC states (5,6,(8)(9)(10). Recently the first biopsy-based human single-cell studies of the kidney and AKI have been reported (8,11,12).…”