Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease

Kidney tissues from cats with naturally occurring chronic kidney disease (CKD) and adult and senior cats without CKD were assessed to determine whether telomere shortening and nitrosative stress are associated with senescence in feline CKD. The histopathologic assessment of percent global glomerulosclerosis, inflammatory infiltrate, and fibrosis was performed. Senescence and nitrosative stress were evaluated utilizing p16 and iNOS immunohistochemistry, respectively. Renal telomere length was evaluated using telomere fluorescent in situ hybridization combined with immunohistochemistry. CKD cats were found to have significantly increased p16 staining in both the renal cortex and corticomedullary junction compared to adult and senior cats. Senior cats had significantly increased p16 staining in the corticomedullary junction compared to adult cats. p16 staining in both the renal cortex and corticomedullary junction were found to be significantly correlated with percent global glomerulosclerosis, cortical inflammatory infiltrate, and fibrosis scores. p16 staining also correlated with age in non-CKD cats. Average telomere length was significantly decreased in CKD cats compared to adult and senior cats. CKD cats had significantly increased iNOS staining compared to adult cats. Our results demonstrate increased renal senescence, telomere shortening, and nitrosative stress in feline CKD, identifying these patients as potential candidates for senolytic therapy with translational potential.

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.

Effects of CREG1 on Age-Associated Metabolic Phenotypes and Renal Senescence in Mice

Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein that accelerates p16-dependent cellular senescence in vitro. We recently reported the ability of CREG1 to stimulate brown adipogenesis using adipocyte P2-CREG1-transgenic (Tg) mice; however, little is known about the effect of CREG1 on aging-associated phenotypes. In this study, we investigated the effects of CREG1 on age-related obesity and renal dysfunction in Tg mice. Increased brown fat formation was detected in aged Tg mice, in which age-associated metabolic phenotypes such as body weight gain and increases in blood glucose were improved compared with those in wild-type (WT) mice. Blood CREG1 levels increased significantly in WT mice with age, whereas the age-related increase was suppressed, and its levels were reduced, in the livers and kidneys of Tg mice relative to those in WT mice at 25 months. Intriguingly, the mRNA levels of Ink4a, Arf, and senescence-associated secretory phenotype (SASP)-related genes and p38MAPK activity were significantly lowered in the aged kidneys of Tg mice, in which the morphological abnormalities of glomeruli as well as filtering function seen in WT kidneys were alleviated. These results suggest the involvement of CREG1 in kidney aging and its potential as a target for improving age-related renal dysfunction.