Cellular Senescence in Repeated Low-Dose Repeated Cisplatin-Induced CKD
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
- Li, Siyao, Central South University, Changsha, Hunan, China
- Livingston, Man J., Augusta University Department of Cellular Biology and Anatomy, Augusta, Georgia, United States
- Dong, Zheng, Augusta University Department of Cellular Biology and Anatomy, Augusta, Georgia, United States
Recent studies have implicated renal tubular cell senescence in the development of chronic kidney pathologies or CKD after acute kidney injury (AKI). Here we investigate the role of cellular senescence in chronic renal injury following cisplatin exposure, and the therapeutic potential of the senolytic drug ABT-263 in cisplatin-induced AKI to CKD progression.
BUMPT cells and C57/B6 Mice were subjected to repeated low-dose cisplatin (RLDC) treatment for in vitro and in vivo studies, respectively. In BUMPT cells, morphological change and senescent markers were measured after RLDC treatment. The conditioned medium derived from control (CT-CM) or RLDC(RLDC-CM) treated BUMPT cells were added to NRK49F fibroblasts to examine the effects on fibroblasts. Following RLDC treatment, BUMPT cells were treated with ABT-263 to investigate its specificity and validity in killing senescent cells. Clonogenic assay was conducted to test the pro-regenerative effect of ABT-263. In vivo, after 4wks of RLDC treatment, mice were given 4 consecutive cycles of ABT-263 injection. Then, GFR was monitored, and the mice were sacrificed 1 day later to collect blood and kidney tissues for analysis.
In Vitro, RLDC induced an enlarged and flatted morphology in BUMPT cells, and decreased cell proliferation. These cells showed notably increased fibrotic markers and typical senescent changes, including positive SA-βgal staining, increases of p21, P53, decreases of LaminB1, and elevated transcription of CDKN1A and CDKN2A. Moreover, RLDC-CM induced higher expression of fibrotic markers in NRK49F cells, indicating the production and secretion of pro-fibrotic factors by RLDC-treated tubular cells. ABT-263 selectively killed senescent cells and promoted cell regeneration as shown by higher clonogenic activities. In Vivo, ABT-263 suppressed the expression of p53, p21 and p16, abolished SA-β gal staining, and decreased the γH2AX+/Ki67- senescent cells. Mice treated with ABT-263 after RLDC showed improved renal function, better kidney structure, and attenuated fibrosis.
Tubular cell senescence is an important factor in the pathogenesis of chronic kidney problems following cisplatin exposure. Clearance of senescent cells by senolytic drugs may be a useful therapeutic strategy for improving kidney repair and functional recovery after cisplatin chemotherapy in cancer patients.
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