Aristolochic Acid Induces Renal Fibrosis and Senescence in Mice

The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

Role of Aberrantly Activated Lysophosphatidic Acid Receptor 1 Signaling Mediated Inflammation in Renal Aging

The increasing load of senescent cells is a source of aging, and chronic inflammation plays a pivotal role in cellular senescence. In addition, senescent renal tubular epithelial cells are closely associated with renal aging. Lysophosphatidic acid (LPA) is a bioactive lipid mainly produced by the catalytic action of autotaxin (ATX), and its ligation to LPA receptor-1 (LPAR1) is associated with chronic inflammation and renal fibrosis; however, its role in renal aging is unclear. Male 2-, 12-, and 24-month-old C57BL/6 mice and Human renal proximal tubular epithelial cells (HRPTEpiC) were used in the present study. DNA damage and oxidative stress-induced senescence were simulated using doxorubicin (DOXO) and H2O2, respectively. The aged kidney showed decreased renal function, increased fractional mesangial area, and tubulointerstitial fibrosis. Both aged kidney and senescent cells showed increased levels of LPAR1, Nuclear factor κB (NF-κB), and inflammatory cytokines. In addition, LPAR1-knockdown reduced NF-κB and subsequent inflammatory cytokine induction, and NF-κB-knockdown resulted in decreased LPAR1 expression. Our study revealed a positive feedback loop between LPAR1 and NF-κB, which reinforces the role of inflammatory response, suggesting that blocking of aberrantly activated LPAR1 may reduce excessive inflammation, thereby providing a new possible therapeutic strategy to attenuate renal aging.

Oxidative stress impairs the Nur77-SIRT1 axis resulting in a decline in organism homeostasis during aging

Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that protects against premature aging and cellular senescence. Aging that is accompanied by oxidative stress leads to a decrease in SIRT1 level and activity, but the regulatory mechanism that connects these events has remained unclear. Here we report that Nur77, an orphan nuclear receptor that shares similar biological pathways with SIRT1, also decreases with age in multiple organs. Our in vivo and in vitro studies revealed that Nur77 and SIRT1 decrease during aging and oxidative stress-induced cellular senescence. Deletion of Nur77 shortens lifespan and accelerates the aging process in multiple mouse tissues. Overexpression of Nur77 protects SIRT1 protein from proteasome degradation through negative transcriptional regulation of the E3 ligase murine double minute 2 (MDM2). Our results show that Nur77 deficiency remarkably aggravates aging related nephropathy, and elucidate a key role for Nur77 in the stabilization of SIRT1 homeostasis during renal aging. We propose a model wherein reduction of Nur77 upon oxidative stress promotes SIRT1 protein degradation through MDM2, which triggers cellular senescence. This creates additional oxidative stress and provides positive feedback for premature aging by further decreasing Nur77 expression. Our findings reveal the mechanism of oxidative stress-reduced SIRT1 during aging and offer an attractive therapeutic strategy for targeting aging organism homeostasis.

DL-3-n-Butylphthalide Alleviates Inflammation and Aging in Advanced Glycation End Products-Induced Mesangial Cells

Age-induced decline in renal function could markedly increase the risk of chronic kidney disease. DL-3-n-butylphthalide (DI-NBP) has notable anti-inflammasome and anti-oxidant effects. However, it’s still unclear whether DI-NBP exerts functions in renal senescence. Thus, the study aims to investigate the effects of DI-NBP on AGE-induced mesangial cells aging and illuminate related pathological process. The cell proliferation levels were detected by CCK8 assay and EDU/DAPI staining, along with the identification of aging-related proteins (β-Gal, p53, p21, p16) by β-Gal staining or Western blot. Intracellular reactive oxygen species (ROS) detection was also performed by ROS kit. In addition, inflammation was evaluated by NLRP3 inflammasome and inflammation-related markers. The results presented increased cell proliferation. Moreover, AGEs-induced cell aging was significantly decreased by DI-NBP, accompanied by decreased ROS levels. Furthermore, DI-NBP reduced NLRP3/caspase1 axis activation and inhibited inflammation in AGEs-induced mesangial cell aging. Thus, DI-NBP might produce significant protective effects on renal aging via decreasing pro-aging-related proteins, oxidative stress and inflammation. DI-NBP could be a potential drug for delaying renal aging.

Aristolochic Acid Nephropathy as a Potential Model of Renal Senescence

The kidney is among the organs most susceptible to age-associated impairments. Although there has recently been extensive research on renal aging, appropriate models remain limited. Generally, renal aging is strongly associated with renal fibrosis, which is the final common pathway of chronic kidney disease. Aristolochic acid (AA), a nephrotoxic agent, causes aristolochic acid nephropathy (AAN), characterized by progressive renal fibrosis and functional decline. Here, we examined the potential of AAN as a model of renal senescence by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group presented aged kidney-like phenotypes such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidney, concomitant with increase in renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, followed by accumulation of reactive oxygen species. Additionally, Klotho, an antiaging gene, was significantly decreased in the kidney of AA-treated mice. Collectively, the results of the present study indicate that AAN partially mimics the aged kidney and may serve as a useful mouse model for research on renal aging.

MO403ACUTE KIDNEY INJURY IN ELDERLY: EPIDEMIOLOGICAL, CLINICAL AND ETIOLOGICAL FEATURES

Background and Aims Acute kidney injury (AKI) is common in the elderly due to physiologic renal aging and underlying pathologies. Few studies focused on AKI in Tunisian elderly. The aim of our study was to highlight the epidemiological, clinical, etiological, therapeutic, and progressive characteristics of AKI in elderly. Method We conducted a descriptive retrospective study of AKI in patients admitted to our department over a period of 04 years from 01/01/2014 to 31/12/2017. Results We collected 40 patients including 25 women and 15 men with a sex ratio of 1.66. The mean age was 74 [65-87] years. We noted the presence of pre-existing chronic kidney disease in 58% of cases, diabetes in 50% of cases and hypertension in 73% of cases. Polypharmacy was found in 40% of cases. AKI was symptomatic in 80% of cases and found on a routine check-up in 20% of cases. Mean creatinine was 612+/-334 µmol/l. AKI was pre-renal in 37% and parenchymal in 63% of cases. Iatrogenic origin was found in 33% of cases. Renal biopsy was performed for diagnostic purposes in 6 cases. Haemodialysis was necessary in 50% of cases. Etiopathogenic treatment was initiated in 73% of cases. Intra-hospital mortality was 10%, recovery of renal function (RF) was partial in 40 % of cases and total in 20 % of cases. Follow-up time was 16 +/- 23.2 months. And at the last news, recovery of renal function (RF) was partial in 7 cases and total in 10 cases, 6 patients kept a chronic renal failure (CRF), among them 3 cases had and end-stage of CRF. Conclusion AKI is a frequent pathology in the elderly and its severity is linked to mortality and the transition to chronicity. Iatrogenic causes are frequent and preventable in this population, hence the major interest of prevention.

Targeting Premature Renal Aging: from Molecular Mechanisms of Cellular Senescence to Senolytic Trials

The biological process of renal aging is characterized by progressive structural and functional deterioration of the kidney leading to end-stage renal disease, requiring renal replacement therapy. Since the discovery of pivotal mechanisms of senescence such as cell cycle arrest, apoptosis inhibition, and the development of a senescence-associated secretory phenotype (SASP), efforts in the understanding of how senescent cells participate in renal physiological and pathological aging have grown exponentially. This has been encouraged by both preclinical studies in animal models with senescent cell clearance or genetic depletion as well as due to evidence coming from the clinical oncologic experience. This review considers the molecular mechanism and pathways that trigger premature renal aging from mitochondrial dysfunction, epigenetic modifications to autophagy, DNA damage repair (DDR), and the involvement of extracellular vesicles. We also discuss the different pharmaceutical approaches to selectively target senescent cells (namely, senolytics) or the development of systemic SASP (called senomorphics) in basic models of CKD and clinical trials. Finally, an overview will be provided on the potential opportunities for their use in renal transplantation during ex vivo machine perfusion to improve the quality of the graft.

Role of tubular epithelial arginase-II in renal inflammaging

The aging kidney undergoes complex changes and is vulnerable to injury and development of chronic kidney disease (CKD) with preponderance affecting more women than men. Evidence has been presented that the type-II L-arginine:ureohydrolase, arginase-II (Arg-II) plays a role in the acceleration of aging. Arg-II is highly expressed in the kidney. However, the role of Arg-II in renal aging is not known. This study is to investigate whether Arg-II is involved in the kidney aging process dependently on sex. Arg-II level in the kidney of wild type (WT) mice is significantly elevated with aging, which is accompanied by an increase in expression of the inflammatory cytokines/chemokines, tissue macrophages, factors involved in fibrosis, and tubulointestitial fibrosis in both males and females. This renal aging phenotype is significantly suppressed in arg-II−/− mice, mainly in the females in which Arg-II level is higher than in the males. Importantly, numerous factors such as IL-1β, MCP1, VCAM-1, and TGFβ1 are mainly localized in the proximal tubular S3 segment cells expressing Arg-II in the aging kidney. In human proximal tubular cells (HK-2), TNF-α enhances adhesion molecule expression dependently on Arg-II upregulation. Overexpression of Arg-II in the cells enhances TGFβ1 levels which is prevented by mitochondrial ROS inhibition. In summary, our study reveals that renal proximal tubular Arg-II plays an important role in the kidney aging process in females. Arg-II could be a promising therapeutic target for the treatment and prevention of aging-associated kidney diseases.