Cellular Senescence: A New Player in Kidney Injury.
Ontology highlight
ABSTRACT:
SUBMITTER: Li Y
PROVIDER: S-EPMC7484413 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Cellular Senescence: A New Player in Kidney Injury.
Li Yongxin Y Lerman Lilach O LO
Hypertension (Dallas, Tex. : 1979) 20200831 4
Kidney diseases secondary to several pathogeneses affect millions of people worldwide and have become increasingly recognized as a global public health problem. Recent evidence suggests that cellular senescence plays an important role in the pathogenesis of different forms of renal damage, including acute and chronic kidney disease, and renal transplantation. Renal senescence involves cell cycle arrest and affects several cellular pathways, manifesting in downregulation of klotho, elevated expre ...[more]
Similar Datasets
Project description:Senescent cells have undergone permanent growth arrest, adopt an altered secretory phenotype, and accumulate in the kidney and other organs with ageing and injury. Senescence has diverse physiologic roles and experimental studies support its importance in nephrogenesis, successful tissue repair, and in opposing malignant transformation. However, recent murine studies have shown that depletion of chronically senescent cells extends healthy lifespan and delays age-associated disease-implicating senescence and the senescence-associated secretory phenotype as drivers of organ dysfunction. Great interest is therefore focused on the manipulation of senescence as a novel therapeutic target in kidney disease. In this review, we examine current knowledge and areas of ongoing uncertainty regarding senescence in the human kidney and experimental models. We summarize evidence supporting the role of senescence in normal kidney development and homeostasis but also senescence-induced maladaptive repair, renal fibrosis, and transplant failure. Recent studies using senescent cell manipulation and depletion as novel therapies to treat renal disease are discussed, and we explore unanswered questions for future research.
| S-EPMC6493983 | biostudies-literature
Project description:Abstract Cellular senescence is a widespread cellular programme that is characterized by permanent cell cycle arrest. Senescent cells adopt a changed secretory phenotype that can alter cellular function. For years, cellular senescence has been thought to be a protective factor against cancer; however, it is now recognized that it has a dual effect on individuals. Co‐ordinated activation of cellular senescence provides advantages during embryogenesis, wound healing, tissue repair and inhibition of tumorigenesis. On the other hand, the aberrant generation and accumulation of abnormal senescent cells lead to the development of age‐related conditions and tissue deterioration. During acute kidney injury (AKI), the kidney faces multiple types of stressors and challenges, which can easily drive cellular senescence. How to appropriately progress through the cell cycle and minimize long‐term damage is of great importance to the acquisition of adaptive repair considering that no available therapeutic interventions can reliably limit injury, speedy recovery or improve the prognosis of this syndrome. Whether the manipulation of cellular senescence can become a novel therapeutic target in AKI and reignite clinical and research interest remains to be determined. Here, we share our current understanding of the role of cellular senescence in AKI, along with examples of the application of mesenchymal stem cells (MSCs) for targeting this disorder during its treatment.
| S-EPMC7812305 | biostudies-literature
Project description:Sepsis-induced acute kidney injury (AKI) can lead to chronic renal dysfunction with accelerated renal aging. Activation of the mammalian target of rapamycin (mTOR) is implicated in the initiation and progression of renal injury. This study investigates the effectiveness of the mTOR inhibitor, rapamycin, in mitigating kidney injury and explores the underlying mechanisms. AKI was induced by intraperitoneal administration of a solution containing 10 mg/kg of lipopolysaccharide (LPS) in a mouse model. Two groups of endotoxemic mice received pre- and post- treatment with rapamycin. Whole-genome DNA methylation analysis was performed on renal proximal tubular epithelial cells (RPTEC). In the LPS-induced AKI mouse model, rapamycin treatment significantly reduced creatinine levels, preserved renal parenchyma, and counteracted the endothelial-to-mesenchymal transition (EndMT) by inhibiting the ERK pathway. Whole-genome DNA methylation analysis revealed that LPS induced aberrant methylation, particularly in genes associated with premature aging, including ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39) and wolframin ER transmembrane glycoprotein (WFS1). Accordingly, endotoxemic mice exhibited decreased CD39 expression and klotho down-regulation, both of which were reversed by rapamycin, suggesting an anti-aging effect in AKI. mTOR inhibition may represent a promising strategy to prevent accelerated renal aging in LPS-induced AKI and potentially slow the progression of chronic kidney disease.
| S-EPMC11926175 | biostudies-literature
Project description:Senescence of kidney tubules leads to tubulointerstitial fibrosis (TIF). Proximal tubular epithelial cells undergo stress-induced senescence during diabetes and episodes of acute kidney injury (AKI), and combining these injuries promotes the progression of diabetic kidney disease (DKD). Since TIF is crucial to progression of DKD, we examined the therapeutic potential of targeting senescence with a senolytic drug (HSP90 inhibitor) and/or a senostatic drug (ASK1 inhibitor) in a model of TIF in which AKI is superimposed on diabetes. After 8 weeks of streptozotocin-induced diabetes, mice underwent bilateral clamping of renal pedicles to induce mild AKI, followed by 28 days of reperfusion. Groups of mice (n=10-12) received either vehicle, HSP90 inhibitor (alvespimycin), ASK1 inhibitor (GS-444217), or both treatments. Vehicle-treated mice displayed tubular injury at day 3 and extensive tubular cell senescence at day 10, which remained unresolved at day 28. Markers of senescence (Cdkn1a and Cdkn2a), inflammation (Cd68, Tnf, and Ccl2), and TIF (Col1a1, Col4a3, α-Sma/Acta2, and Tgfb1) were elevated at day 28, coinciding with renal function impairment. Treatment with alvespimycin alone reduced kidney senescence and levels of Col1a1, Acta2, Tgfb1, and Cd68; however, further treatment with GS-444217 also reduced Col4a3, Tnf, Ccl2, and renal function impairment. Senolytic therapy can inhibit TIF during DKD, but its effectiveness can be improved by follow-up treatment with a senostatic inhibitor, which has important implications for treating progressive DKD.
| S-EPMC10914710 | biostudies-literature
Project description:PurposeAcute kidney injury (AKI) secondary to Rhabdomyolysis syndrome represents a life-threatening complication, characterized by notably high incidence and mortality rates. The role of cellular senescence in the progression of AKI has increasingly garnered attention in recent years. Our previous research has demonstrated that remote ischemic postconditioning (RIPC) can attenuate renal cellular senescence and elevation of serum level of interleukin-6 (IL-6) induced by ischemia-reperfusion injury following crush injury. The objective of this study is to investigate the specific role of IL-6 in Rhabdomyolysis-induced AKI (RM-AKI).MethodsWe established a mouse model of RM-AKI by intramuscular injection of glycerol and simulated RM-AKI at the cellular level by treating Hk-2 cells with myoglobin. Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, is a key substance. IL-6, a multifunctional cytokine, plays a crucial role in the occurrence and development of various kidney diseases. It can promote inflammatory responses, cell proliferation, fibrosis, and other processes. TCZ exerts a protective effect on the kidneys by specifically binding to the IL-6 receptor and blocking the signal transduction of IL-6. Additionally, the levels of IL-6 were detected by employing ELISA kits. RNA sequencing analysis was performed on cells treated with myoglobin and tocilizumab. Flow cytometry was utilized to assess cell cycle distribution and the percentage of senescent cells. The expression levels of SERPINE1, GATA2, p53, and p21 were determined by real-time quantitative PCR and Western blot. Additionally, a dual-luciferase reporter gene assay was conducted to validate the binding effect of SERPINE1 and GATA2.ResultsTranscriptome Analysis revealed that genes including GATA2 and SERPINE1 were downregulated in HK-2 cells following tocilizumab treatment. Inhibition of the IL-6 receptor by tocilizumab in these cells led to a reduction in cellular senescence, accompanied by decreased of the cell cycle regulatory proteins P53 and P21 in mRNA and protein levels, while alleviating cell cycle arrest. Additionally, a dual-luciferase reporter assay confirmed that GATA2 binds to the promoter of SERPINE1 (PAI-1), thereby initiating its transcription.ConclusionThe IL-6/GATA2/SERPINE1 pathway mediates cellular senescence after acute kidney injury, and inhibiting IL-6 can alleviate AKI-induced cellular senescence, providing an important basis for exploring new therapeutic strategies.
| S-EPMC11850272 | biostudies-literature
Project description:Acute kidney injury (AKI) is one of the serious clinical syndromes with high morbidity and mortality. Despite substantial progress in understanding the mechanism of AKI, no effective drug is available for treatment or prevention. In this study, we identified that a ligand-activated transcription factor aryl hydrocarbon receptor (AhR) was abnormally increased in the kidneys of cisplatin-induced AKI mice or tubular epithelial TCMK-1 cells. The AhR inhibition by BAY2416964 and tubular conditional deletion both alleviated cisplatin-induced kidney dysfunction and tubular injury. Notably, inhibition of AhR could improve cellular senescence of injured kidneys, which was indicated by senescence-associated β-galactosidase (SA-β-gal) activity, biomarker p53, p21, p16 expression, and secretory-associated secretory phenotype IL-1β, IL-6 and TNFα level. Mechanistically, the abnormal AhR expression was positively correlated with the increase of a methyltransferase EZH2, and AhR inhibition suppressed the EZH2 expression in cisplatin-injured kidneys. Furthermore, the result of ChIP assay displayed that EZH2 might indirectly interact with AhR promoter region by affecting H3K27me3. The direct recruitment between H3K27me3 and AhR promoter is higher in the kidneys of control than that of cisplatin-treated mice, suggesting EZH2 reversely influenced AhR expression through weakening H3K27me3 transcriptional inhibition on AhR promoter. The present study implicated that AhR and EZH2 have mutual regulation, which further accelerated tubular senescence in cisplatin-induced AKI. Notably, the crucial role of AhR is potential to become a promising target for AKI.
| S-EPMC9837170 | biostudies-literature
Project description:BackgroundDysregulations in cholesterol and lipid metabolism have been linked to human diseases like hypercholesterolemia, atherosclerosis or the metabolic syndrome. Many ABC transporters are involved in trafficking of metabolites derived from these pathways. Pseudoxanthoma elasticum (PXE), an autosomal-recessive disease caused by ABCC6 mutations, is characterized by atherogenesis and soft tissue calcification.MethodsIn this study we investigated the regulation of cholesterol biosynthesis in human dermal fibroblasts from PXE patients and healthy controls.ResultsGene expression analysis of 84 targets indicated dysregulations in cholesterol metabolism in PXE fibroblasts. Transcript levels of ABCC6 were strongly increased in lipoprotein-deficient serum (LPDS) and under serum starvation in healthy controls. For the first time, increased HMG CoA reductase activities were found in PXE fibroblasts. We further observed strongly elevated transcript and protein levels for the proprotein convertase subtilisin/kexin type 9 (PCSK9), as well as a significant reduction in APOE mRNA expression in PXE.ConclusionIncreased cholesterol biosynthesis, elevated PCSK9 levels and reduced APOE mRNA expression newly found in PXE fibroblasts could enforce atherogenesis and cardiovascular risk in PXE patients. Moreover, the increase in ABCC6 expression accompanied by the induction of cholesterol biosynthesis supposes a functional role for ABCC6 in human lipoprotein and cholesterol homeostasis.
| S-EPMC4124508 | biostudies-literature
Project description:Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFβ as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies.
| S-EPMC5844882 | biostudies-literature
Project description:Sepsis is a severe and dysregulated inflammatory disease that often precedes the development of acute kidney injury (AKI) with consequent worsening outcome. The main characteristics of sepsis-induced AKI include endothelial cell (EC) dysfunction, infiltration of inflammatory cells, glomerular thrombosis, and renal tubular epithelial cells (RTEC) injury. Numerous studies have demonstrated that mammalian target of rapamycin (mTOR) activation has been implicated in the initiation and progression of renal injury in course of sepsis. However, little is known, about the molecular basis of mTOR role in EC and RTEC dysfunction. Here, we evaluate whether mTOR inhibition by Rapamycin (Rp) as potential strategy to ameliorate renal function and dissected the molecular mechanisms involved. In a mouse model of lipopolysaccharide (LPS)-induced AKI , LPS injection led to a time-dependent increase of serum creatinine and significant morphological changes in renal parenchyma associated with increased collagen deposits and endothelial dysfunction. Interestingly, Rp treatment significantly decreased creatine levels and preserved renal parenchyma, counteracting Endothelial-to mesenchymal transition (EndMT) process and early fibrosis through the inhibition of ERK pathway. Next, we examined the effects of LPS-TLR4 interaction in RTECs. Through a whole-genome DNA methylation analysis in cultured RTEC, we found that LPS induced aberrant methylation, particularly in regions involved in premature aging. The most represented genes were CD39 and WFS1. LPS stimulation of RTEC led to up-regulation of SA-β Gal and cell cycle arrest markers such as p21. In accordance, in endotoxemic mice, we found a decreased expression of CD39 concurrent with Klotho down-regulation. Administration of Rp exerted anti-aging effects in endotoxemic mice, preserving CD39 and Klotho expression. In conclusion, we demonstrated that mTOR inhibition could offer novel strategies to protect endothelial and tubular compartment from accelerated aging and fibrosis thus counteracting the progression to chronic kidney disease.
2024-09-16 | E-MTAB-13396 | biostudies-arrayexpress
Project description:Chronic kidney disease (CKD) is an increasing health burden (affecting approximately 13.4% of the population). Currently, no curative treatment options are available and treatment is focused on limiting the disease progression. The accumulation of senescent cells has been implicated in the development of kidney fibrosis by limiting tissue rejuvenation and through the secretion of pro-fibrotic and pro-inflammatory mediators termed as the senescence-associated secretory phenotype. The clearance of senescent cells in aging models results in improved kidney function, which shows promise for the options of targeting senescent cells in CKD. There are several approaches for the development of "senotherapies", the most rigorous of which is the elimination of senescent cells by the so-called senolytic drugs either newly developed or repurposed for off-target effects in terms of selectively inducing apoptosis in senescent cells. Several chemotherapeutics and checkpoint inhibitors currently used in daily oncological practice show senolytic properties. However, the applicability of such senolytic compounds for the treatment of renal diseases has hardly been investigated. A serious concern is that systemic side effects will limit the use of senolytics for kidney fibrosis. Specifically targeting senescent cells and/or targeted drug delivery to the kidney might circumvent these side effects. In this review, we discuss the connection between CKD and senescence, the pharmacological options for targeting senescent cells, and the means to specifically target the kidney.
| S-EPMC6639430 | biostudies-literature