AI Article Synopsis

  • Emerging evidence indicates that cellular senescence plays a crucial role in chronic kidney disease (CKD), with proximal tubule epithelial cells (PTECs) and fibroblasts being key contributors to this condition.
  • Researchers developed a new human kidney cell model by isolating PTECs and fibroblasts and introducing a specific viral vector, allowing them to better mimic real kidney cells and study their behaviors.
  • The study found that senescent PTECs can trigger fibrosis in fibroblasts, and the presence of p21-positive cells in kidney sections correlated with more severe fibrosis and reduced kidney function, thereby underscoring the importance of cellular senescence in CKD.

Article Abstract

Emerging evidence highlights cellular senescence's pivotal role in chronic kidney disease (CKD). Proximal tubule epithelial cells (PTECs) and fibroblasts are major players in CKD and serve as cellular sources of senescence. The generation of a conditionally immortalized human kidney cell model would allow to better understand the specific mechanisms and factors associated with cellular senescence in a controlled setting, devoid of potential confounding factors such as age and comorbidities. In addition, the availability of human kidney cell lines for preclinical research is sparse and most cell lines do not reflect their in vivo counterparts due to their altered behavior as immortalized cancer-like cells. In this study, PTECs and fibroblasts from human kidneys were isolated and transduced with doxycycline-inducible simian virus 40 large T antigen (SV40LT) vector. By comparing their gene expression with single-cell RNA sequencing data from human kidneys, the newly produced human kidney cell lines demonstrated significant resemblances to their in vivo counterparts. As predicted, PTECs showed functional activity and fibroblasts responded to injury with fibrosis. Withdrawal of the immortalizing factor doxycycline led to p21 cell-cycle arrest and the key hallmarks of senescence. The obtained senescence gene set largely overlapped between both cell lines and with the previously published SenMayo set of senescence-associated genes. Furthermore, crosstalk experiments showed that senescent PTECs can cause a profibrotic response in fibroblasts by paracrine actions. In 76 human kidney sections, the number of p21 cells correlated with the degree of fibrosis, age and reduced glomerular filtration, validating the role of senescence in CKD. In conclusion, we provide a novel cellular ex vivo model to study kidney senescence which can serve as a platform for large scale compounds testing.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324798PMC
http://dx.doi.org/10.1038/s41420-024-02131-yDOI Listing

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