p53 in Proximal Tubules Mediates Chronic Kidney Problems after Cisplatin Treatment

Abstract

Nephrotoxicity is a major side-effect of cisplatin in chemotherapy, which can occur acutely or progress into chronic kidney disease (CKD). The protein p53 plays an important role in acute kidney injury induced by cisplatin, but its involvement in CKD following cisplatin exposure is unclear. Here, we address this question by using experimental models of repeated low-dose cisplatin (RLDC) treatment. In mouse proximal tubular BUMPT cells, RLDC treatment induced p53 activation, apoptosis, and fibrotic changes, which were suppressed by pifithrin-α, a pharmacologic inhibitor of p53. In vivo, chronic kidney problems following RLDC treatment were ameliorated in proximal tubule-specific p53-knockout mice (PT-p53-KO mice). Compared with wild-type littermates, PT-p53-KO mice showed less renal damage (KIM-1 positive area: 0.97% vs. 2.5%), less tubular degeneration (LTL positive area: 15.97% vs. 10.54%), and increased proliferation (Ki67 positive area: 2.42% vs. 0.45%), resulting in better renal function after RLDC treatment. Together, these results indicate that p53 in proximal tubular cells contributes significantly to the development of chronic kidney problems following cisplatin chemotherapy.

Impact of Gum acacia on oxidative stress and apoptosis in Adenine-induced CKD animal model

“…Contrarily, rats given GA showed reduced levels of p53, Bax, and caspase-3 along with an increase in the anti-apoptotic markers Bcl-2. Previous research revealed that the pro-apoptotic protein Bax can be directly activated by p53 to start apoptosis through the mitochondrial route [22],, which significantly aids in the development of CKD [23] [24]. The mitochondrial cell death pathway is caused by malfunctioning mitochondria, which show membrane depolarization and fragmentation, high levels of ROS production, and the release of apoptogenic proteins (such as caspase-3) in response to stimuli [24].…”

“…Previous research revealed that the pro-apoptotic protein Bax can be directly activated by p53 to start apoptosis through the mitochondrial route [22],, which significantly aids in the development of CKD [23] [24]. The mitochondrial cell death pathway is caused by malfunctioning mitochondria, which show membrane depolarization and fragmentation, high levels of ROS production, and the release of apoptogenic proteins (such as caspase-3) in response to stimuli [24]. Cell death is delayed as a result of the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein's ability to stop the activation of apoptotic caspases in the mitochondria [25].…”

Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

“…It has been reported that weekly intraperitoneal injection of low-dose cisplatin for 4 weeks can create a robust model of CKD [ 50 , 51 ]. However, the end point analysis of kidney function and measurement of kidney functional parameters after low-dose cisplatin induction of CKD can range from weeks to months [ 51 , 52 ]. It should be pointed out that many cisplatin studies using rodent models only involve healthy animals, instead of animals bearing cancers or tumors.…”

“…The general mechanisms of these natural products are summarized in Figure 5 . These include blockage of cisplatin renal uptake and transportation [ 22 ], inhibition of oxidative stress [ 96 , 97 ], inhibition of inflammation [ 98 , 99 ], inhibition of P53 signaling pathways [ 52 ], inhibition of mitogen-activated protein kinases [ 100 ], attenuation of cell death, and enhancement of cellular antioxidant defense systems such as SOD, catalase, and the Nrf2 pathway [ 101 , 102 ]. Autophagy and mitophagy are also involved in cisplatin-induced kidney injury [ 51 , 103 ] and can be modulated by natural products for protective purposes [ 104 , 105 , 106 , 107 ].…”

MicroRNA-34a: A Novel Therapeutic Target in Fibrosis

“…MiR-34a is the direct transcription target of p53, and can negatively regulate sirtuin 1(SIRT1), resulting in increased p53 acetylation. P53 and SIRT1 are typical genes involved in apoptosis regulation ( Yamakuchi et al, 2008 ; Li et al, 2011 ), and p53 is a major contributor to the onset and progression of fibrotic diseases ( Yang et al, 2010 ; Sutton et al, 2013 ; Overstreet et al, 2014 ; Valentijn et al, 2021 ; Fu et al, 2022 ; Li et al, 2022 ). Therefore, the miR-34a SIRT1/p53 signaling pathway forms a positive feedback loop that has a vital role in cell proliferation and apoptosis ( Tarasov et al, 2007 ; Kumamoto et al, 2008 ; Kim et al, 2015 ).…”