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.
Highlights
Published: 11 February 2022Kidney diseases such as acute kidney injury (AKI) and chronic kidney disease (CKD)are a worldwide health problem
While AKI describes a sudden loss of renal function and can be caused by diverse conditions such as sepsis, nephrotoxicity or ischemia-reperfusion injury (IRI) [1], CKD is defined as a gradual deprivation of kidney function over a time period of more than three months [2]
Kidney organoids of three iPS cell lines in duplicates were generated in approximately 20 days (Figure 1a; Table 1)
Summary
Published: 11 February 2022Kidney diseases such as acute kidney injury (AKI) and chronic kidney disease (CKD)are a worldwide health problem. While AKI describes a sudden loss of renal function and can be caused by diverse conditions such as sepsis, nephrotoxicity or ischemia-reperfusion injury (IRI) [1], CKD is defined as a gradual deprivation of kidney function over a time period of more than three months [2]. Major causes of CKD include diabetes and hypertension as well as oxidative stress and inflammation [2,3]. The progression of CKD leads to end-stage renal disease (ESRD) requiring dialysis or organ transplantation [4]. CKD and AKI, various conditions such as diabetes, hypertension and obesity can lead to the emergence of ESRD [5]. The glomerular barrier consists of a basement membrane, endothelial cells and intertwined podocytic foot processes [5]. Part of the filtration barrier is formed by slit diaphragms, assembled by podocyte-associated proteins nephrin, podocin, synaptopodin, CD-2-associated protein (CD2AP) and the zonula occludens protein-1 (ZO-1) [7].
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