Modelling acute kidney injury on iPSC derived organoids

Abstract

The kidneys are crucial organs for the balance of fluids and excretion of wastes. However, their excretory role renders them vulnerable to drug-induced toxicity, for example by the chemotherapeutic drug cisplatin. Nephrotoxic side effects of cisplatin manifest in acute kidney injury (AKI), an abrupt loss of kidney function. AKI is strongly associated with the progression to chronic kidney disease (CKD) and renal fibrosis, and in severe cases end stage renal disease (ESRD) requiring dialysis or kidney transplantation. Currently, no treatments for AKI or successful interventions to stop the progression of renal injury to more serious forms of impairment are available. This is in part due to the lack of clinically translatable models of cisplatin-induced AKI. In this work, I have taken advantage of the recently developed method of growing kidney organoids, 'mini kidneys' in a dish, from human induced pluripotent stem cells (iPSCs) to model cisplatin-induced AKI. Kidney organoids closely resemble human kidney tissue and can be produced in large-scale, which enabled me to assess the effects of cisplatin systematically. Organoids were treated with different regimens of cisplatin to cover a range of doses and exposure times. My results showed that cisplatin induced injury markers as well as DNA damage and apoptosis resembling the symptoms found in AKI patients, however damage specific to the proximal tubule, the primary target structure of cisplatin, was not obvious. Instead, my data suggested that cisplatin preferentially targeted proliferating cells in the organoids, thereby reflecting the anti-cancer effects of the drug. Importantly, a robust inflammatory response and evidence of fibrosis was observed, suggesting that cisplatin-treated organoids possibly recapitulate development of renal fibrosis, a hallmark of CKD. Furthermore, in a proof-of-principle approach, I demonstrated that co-treatment of cisplatin with the small molecule inhibitor JQ1 ameliorated the damage inflicted by cisplatin. Taken together, my work demonstrates that kidney organoids recapitulate acute kidney injury when exposed to cisplatin and can be used as a platform for the development of novel therapeutic interventions in AKI to CKD progression.