Senolytic therapy ameliorates renal fibrosis postacute kidney injury by alleviating renal senescence

Abstract

Acute kidney injury (AKI) is a common clinical problem, and patients who survive AKI have a high risk of chronic kidney disease (CKD). The mechanism of CKD post‐AKI, characterized by progressive renal fibrosis, is still unclear. Maladaptive tubular epithelial cells (TECs) after AKI are considered a leading cause of renal fibrosis post‐AKI. TECs under maladaptive repair manifest characteristics of senescence. Removing senescent TECs by genetic ablation has been proven effective in reducing renal fibrosis. Senolytics, which eliminate senescent cells by pharmacological intervention, have been studied in a series of degenerative diseases. To our knowledge, the effects of senolytics on renal fibrosis post‐AKI have not been verified before. Here, we confirmed renal senescence in the unilateral ischemia/reperfusion injury murine model. Senescent TECs could activate fibroblasts and senolytics specifically induced apoptosis of senescent TECs. Next, we demonstrated that senolytics could reduce renal senescence and ameliorate renal fibrosis in both unilateral renal ischemia/reperfusion injury and multiple‐cisplatin‐treatment murine models. Our results indicate senescent TECs as a vital factor in renal fibrosis progression, and senolytic therapy might be promising for treating CKD post‐AKI.

Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice

“…Senescent cell killing compounds, termed senolytics, are a new category of pharmaceuticals aimed at combating age‐associated diseases, systemically clearing senescent cells by removing the brakes on senescent cell anti‐apoptotic pathways (SCAPs) (Zhu et al, 2015 , 2016 ). The combination of dasatinib and quercetin is especially effective at removing senescent cells in a host of tissues (Chu et al, 2020 ; Li et al, 2021 ; Palmer et al, 2019 ; Zhang, Swarts, et al, 2019 ; Zhu et al, 2015 ), all while improving physical function and extending lifespan (Xu et al, 2018 ). Although there are conflicting reports on the abundance of senescent cells in resting muscle from old mice (Dungan et al, 2020 ; Silva et al, 2019 ), recent studies have demonstrated that 10 days following cardiotoxin injury to muscle, senolytic drugs elevate satellite cell numbers and are associated with a greater number of large myofibers (Doan et al, 2020 ), in addition to reducing the number of SA β‐Gal+ cells in damaged muscle tissue (Chiche et al, 2017 ).…”

Autophagy in Cisplatin Nephrotoxicity during Cancer Therapy

“…Thus, the glomerular injury may occur after tubular injury [ 58 ]. Finally, antioxidant [ 60 ] and anti-senescence compounds [ 61 , 62 ] partially delayed CKD progression after RLDC treatment, suggesting the involvement of reactive oxygen species and cell senescence in the pathogenesis.…”

“…Baisantry et al [ 15 ] demonstrated that Atg5 ablation from kidney proximal tubules decreased tubular cell senescence and reduced fibrosis after renal ischemia/reperfusion injury in mice, implying a role of tubular autophagy in senescence and renal fibrosis in post-injury kidneys. More recently, senescent cells in kidneys after repeated low dose cisplatin treatment, which, along with fibrosis, was alleviated by NAC [ 62 ] and intermittent Dasatinib + Quercetin treatment [ 61 ].…”

Epigenetic Modification Drives Acute Kidney Injury-to-Chronic Kidney Disease Progression

“…In the past, AKI was thought to be a reversible disease but recent studies show that 20-50% of AKI survivors will progress to chronic kidney disease (CKD) [4]. Patients with AKI may develop CKD, even end-stage kidney disease, even if there is no history of kidney disease, or renal function has partially or fully recovered [4][5][6][7][8][9]. Compared with those without AKI, patients with AKI had an approximately 8-fold increased risk of developing CKD and 3-fold of developing end-stage kidney disease [10].…”