Modelling AKI in vitro: taking organoids to the next level

Repeated episodes of acute kidney injury (AKI) can lead to chronic kidney disease (CKD). The proximal tubule (PT) is particularly vulnerable to injury because it plays a crucial metabolic role in the handling of drugs, nephrotoxins, metabolites, and signaling molecules. Despite some regenerative potential of PT epithelial cells, the kidney has a limited capacity for repair after injury. When the injury exceeds this capacity, unresolved tubular lesions lead to nephron loss accompanied by fibrosis. Currently, no pharmacologic strategy can prevent disease progression from AKI to CKD, in part due to the lack of a comprehensive understanding of pathologic mechanisms underlying the AKI-to-CKD transition. Studies in animal models have provided compelling evidence that DNA damage response (DDR) is central to PT repair following injury. Ataxia telangiectasia and Rad3-related protein (ATR), a critical sensor and initiator of the DDR-signaling cascade, is activated in the PT of patients with CKD and in mouse models of tubular injury. PT-specific deletion of ATR results in persistently unrepaired DNA damage that leads to G2/M cell cycle arrest, senescence, and ultimately apoptosis, promoting AKI-to-CKD transition. Other studies have questioned the association between G2/M cell cycle arrest and failed PT repair and have proposed alternative buffering mechanisms against DNA damage. Whether DDR signaling represents a targetable pathway for preventing CKD in humans remains to be illustrated in relevant models. Human pluripotent stem cell (hPSC)–derived kidney organoids recapitulate multiple spatiotemporal processes observed in the developing human kidney, although they manifest only rudimentary function. In response to nephrotoxins, kidney organoids upregulate the expression of kidney injury molecule 1 (KIM1) in PT. Furthermore, cisplatin treatment of kidney organoids activated ATR in PT epithelial cells that harbor damaged DNA. Harnessing the potential physiological relevance of human kidney organoids, Gupta et al. recently identified the DDR protein Fanconi anemia complementation group D2 (FANCD2) as a conserved critical modulator of tubular repair in both mouse and human.