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The Nephrotoxin Puromycin Aminonucleoside Induces Injury in Kidney Organoids Differentiated from Induced Pluripotent Stem Cells.

ABSTRACT: Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), which can progress to end stage renal disease (ESRD), are a worldwide health burden. Organ transplantation or kidney dialysis are the only effective available therapeutic tools. Therefore, in vitro models of kidney diseases and the development of prospective therapeutic options are urgently needed. Within the kidney, the glomeruli are involved in blood filtration and waste excretion and are easily affected by changing cellular conditions. Puromycin aminonucleoside (PAN) is a nephrotoxin, which can be employed to induce acute glomerular damage and to model glomerular disease. For this reason, we generated kidney organoids from three iPSC lines and treated these with PAN in order to induce kidney injury. Morphological observations revealed the disruption of glomerular and tubular structures within the kidney organoids upon PAN treatment, which were confirmed by transcriptome analyses. Subsequent analyses revealed an upregulation of immune response as well as inflammatory and cell-death-related processes. We conclude that the treatment of iPSC-derived kidney organoids with PAN induces kidney injury mediated by an intertwined network of inflammation, cytoskeletal re-arrangement, DNA damage, apoptosis and cell death. Furthermore, urine-stem-cell-derived kidney organoids can be used to model kidney-associated diseases and drug discovery.

SUBMITTER: Nguyen L

PROVIDER: S-EPMC8870209 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The nephrotxin Puromycin aminonucleoside induces injury in kidney organoids differentiated from human urine SIX2-positive stem cell derived induced pluripotent stem cells.

Project description:Kidney diseases including acute kidney injury (AKI) and chronic kidney disease (CKD), which can progress to end stage renal disease (ESRD), are a worldwide health burden. Organ trans-plantation or kidney dialysis are the only effective available therapeutic tools. Therefore, in vitro models of kidney diseases and the development of prospective therapeutic means are highly demanded. Within the kidney, the glomeruli are involved in blood filtration and waste excre-tion, and are easily affected by changing cellular conditions. Puromycin aminonucleoside (PAN) is a nephrotoxin, which can be harnessed for imitating acute glomerular damage and modelling of glomerular disease. For this reason, we generated kidney organoids from three iPSC lines and treated these with PAN in order to induce kidney injury. Morphological observations re-vealed disruption of glomerular and tubular structures within the kidney organoids upon PAN treatment, which were confirmed by transcriptome analyses. Subsequent analyses revealed an upregulation of immune response as well as inflammatory and cell death-related processes. We concluded that treatment of iPSC-derived kidney organoids with PAN induces kidney injury mediated an intertwined network of inflammation, cytoskeletal re-arrangement, DNA damage, apoptosis and cell death. Furthermore, urine stem cell-derived kidney organoids can be used for modelling of kidney-associated diseases and drug discovery.

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The nephrotxin Puromycin aminonucleoside induces injury in kidney organoids differentiated from human urine SIX2-positive stem cell derived induced pluripotent stem cells.

Project description:The nephrotxin Puromycin aminonucleoside induces injury in kidney organoids differentiated from human urine SIX2-positive stem cell derived induced pluripotent stem cells.

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Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models.

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