Project description:Reduction in blood supply to the kidneys occurs to certain extent during acute kidney injury (AKI). Individuals who suffered AKI are at risk of developing chronic kidney disease (CKD) through a maladaptive repair process. Currently, the lack of a reliable research model that allows the characterization of the maladaptive regeneration during such transition, impedes the development of effective therapies. Here, we present the first human kidney organoid model that physiologically and morphologically resembles the AKI and the maladaptive regeneration. Kidney organoids were generated from human induced pluripotent stem cells. After 18 days of grow the organoids were under hypoxic conditions for 2 days to simulate AKI. Organoids were collected at day 20 to assess hypoxic injury, and after a 5-day recovery in normoxic conditions to assess maladaptive repair. The transcriptome, proteome and metabolome were profiled. Gene expression analysis of day 20 hypoxic organoids identified signatures of injury, cell death (necroptosis and ferroptosis), cell cycle arrest and changes in metabolism. The maladaptive repair phenotype was supported by enrichment of pathways associated with inflammatory signals, oxidative stress, and tissue remodelling. Specific genes associated with kidney injury and disease such as GDF15, MMP7, ICAM1, TGFB1, CCN1, C3 and S100A8/9 were upregulated. Single-cell RNA sequencing localized expression of maladaptive repair genes and activation of TNF and JAK-STAT signalling pathways specific to tubular epithelial cells. Dysregulation in metabolic pathways such as glycolysis and gluconeogenesis, amino acid and lipid metabolisms were conserved in this model. Altogether, these results support the use of kidney organoids as a model of AKI and early CKD that can be used for biomarker validation, elucidation of pathological mechanisms, and drug screening.
Project description:Chronic kidney disease (CKD) affects over half of all adults over 70 and 13% of the global population. The development of renal fibrosis is strongly correlated with loss of kidney function during CKD and involves cellular injury, excessive production of extracellular matrix proteins and inflammation. Current treatments focus on controlling blood pressure, controlling diabetes, and steroid therapies; however, we have no treatments to suppress renal fibrosis. Because hypoxia plays a key role in the development and progression of CKD, we have developed a new model of induced pluripotent stem cell-derived kidney organoids to study in vitro the development of fibrosis in a human model.
Project description:Purpose of reviewDespite improvements in acute kidney injury (AKI) detection, therapeutic options to halt the progression of AKI to chronic kidney disease (CKD) remain limited. In this review, we focus on recent discoveries related to the pathophysiology of the AKI to CKD continuum, particularly involving the renal tubular epithelial cells, and also discuss related ongoing clinical trials. While our focus is on injured renal tubular epithelial cells as initiators of the cascade of events resulting in paracrine effects on other cells of the kidney, the summation of maladaptive responses from various kidney cell types ultimately leads to fibrosis and dysfunction characteristic of CKD.Recent findingsRecent findings that we will focus on include, but are not limited to, characterizations of: the association between cell cycle arrest and cellular senescence in renal tubular epithelial cells and its contribution to renal fibrosis, chronic inflammation with persistent cytokine production and lymphocyte infiltration among unrepaired renal tubules, mitochondrial dysfunction and a unique role of cytosolic mitochondria DNA in fibrogenesis, prolyl hydroxylase domain proteins as potential therapeutic targets, and novel mechanisms involving the Hippo/yes-associated protein/transcriptional coactivator with PDZ-binding pathway.SummaryPotential therapeutic options to address CKD progression will be informed by a better understanding of fibrogenic pathways. Recent advances suggest additional drug targets in the various pathways leading to fibrosis.
