Treadmill Exercise Training Ameliorates Functional and Structural Age-Associated Kidney Changes in Male Albino Rats

Aging is a biological process that impacts multiple organs. Unfortunately, kidney aging affects the quality of life with high mortality rate. So, searching for innovative nonpharmacological modality improving age-associated kidney deterioration is important. This study aimed to throw more light on the beneficial effect of treadmill exercise on the aged kidney. Thirty male albino rats were divided into three groups: young (3-4 months old), sedentary aged (23-24 months old), and exercised aged (23-24 months old, practiced moderate-intensity treadmill exercise 5 days/week for 8 weeks). The results showed marked structural alterations in the aged kidney with concomitant impairment of kidney functions and increase in arterial blood pressure with no significant difference in kidney weight. Also, it revealed that treadmill exercise alleviated theses effects in exercised aged group with reduction of urea and cystatin C. Exercise training significantly decreased glomerulosclerosis index, tubular injury score, and % area of collagen deposition. Treadmill exercise exerted its beneficial role via a significant reduction of C-reactive protein and malondialdehyde and increase in total antioxidant capacity. In addition, exercise training significantly decreased desmin immunoreaction and increased aquaporin-3, vascular endothelial growth factor, and beclin-1 in the aged kidney. This study clarified that treadmill exercise exerted its effects via antioxidant and anti-inflammatory mechanisms, podocyte protection, improving aquaporin-3 and vascular endothelial growth factor expression, and inducing autophagy in the aged kidney. This work provided a new insight into the promising role of aerobic exercise to ameliorate age-associated kidney damage.

Podocyte Aging: Why and How Getting Old Matters

The effects of healthy aging on the kidney, and how these effects intersect with superimposed diseases, are highly relevant in the context of the population’s increasing longevity. Age-associated changes to podocytes, which are terminally differentiated glomerular epithelial cells, adversely affect kidney health. This review discusses the molecular and cellular mechanisms underlying podocyte aging, how these mechanisms might be augmented by disease in the aged kidney, and approaches to mitigate progressive damage to podocytes. Furthermore, we address how biologic pathways such as those associated with cellular growth confound aging in humans and rodents.

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.

Podocyte Aging: Why and How Getting Old Matters

The effects of healthy aging on the kidney, and how these effects intersect with superimposed diseases, are highly relevant in the context of the population's increasing longevity. Age-associated changes to podocytes, which are terminally differentiated glomerular epithelial cells, adversely affect kidney health. This review discusses the molecular and cellular mechanisms underlying podocyte aging, how these mechanisms might be augmented by disease in the aged kidney, and approaches to mitigate progressive damage to podocytes. Furthermore, we address how biologic pathways such as those associated with cellular growth confound aging in humans and rodents.

The Aging Kidney—As Influenced by Heavy Metal Exposure and Selenium Supplementation

The aging process in the kidneys has been well studied. It is known that the glomerular filtration rate (GFR) declines with age in subjects older than 50–60 years. However, there is still insufficient knowledge regarding the response of the aged kidney to environmental toxicants such as mercury, cadmium, and lead. Here, we present a review on the functional decline and proposed mechanisms in the aging kidney as influenced by metal pollutants. Due to the prevalence of these toxicants in the environment, human exposure is nearly unavoidable. Further, it is well known that acute and chronic exposures to toxic metals may be detrimental to kidneys of normal adults, thus it may be hypothesized that exposure of individuals with reduced GFR will result in additional reductions in renal function. Individuals with compromised renal function, either from aging or from a combination of aging and disease, may be particularly susceptible to environmental toxicants. The available data appear to show an association between exposure to mercury, cadmium and/or lead and an increase in incidence and severity of renal disease in elderly individuals. Furthermore, some physiological thiols, as well as adequate selenium status, appear to exert a protective action. Further studies providing improved insight into the mechanisms by which nephrotoxic metals are handled by aging kidneys, as well as possibilities of therapeutic protection, are of utmost importance.

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.

P0552EXPRESSION OF CNDP1 PROTEIN IS REGULATED BY AGE-DEPENDENT AND AKI-RELATED ASTRAGALUS MEMBRANACEOUS EFFECTS IN MICE

Background and Aims Astragalus membranaceus (AM) is widely used for herbal medicine in Asia (see http://nccih.nih.gov/health/astragalus). Until now, numerous findings about the AM effects have been provided in various tissues and organs; however, the therapeutic effects of AM against chronic kidney disease (CKD) remain unclear. Recent findings suggest that acute kidney injury (AKI), which has been previously believed to heal completely, is a promoting factor for CKD pathogenesis or progression. Our recent findings have been observed that susceptibility to AKI as well as AM effects against AKI was significant in old mice, suggesting that AM effects exert an age-dependent manner in kidney. Therefore, we further examined the therapeutic effect of AM against age-dependent AKI pathogenicity. Method Female C57BL/6 mice were collected blood in advance (0.2 ml as normal), separated to two groups, and administered with AM powder-mixed sterilized 0.5% methylcellulose 400 (w/v) (AM-administered group) or with sterilized 0.5% methylcellulose 400 (control group), respectively by two hours before surgery. Left renal artery was exposed and occluded by non-traumatic small clips for 20 minutes. Twenty hours after the renal reperfusion, we collected blood (0.2 ml as reaction) and acquired kidney from each mouse. These serum samples were measured to detect serum creatinine and urea nitrogen. The dissected kidneys were used for Western blot analysis to determine the expression of AM-target protein candidates, which were selected as both age-dependent and renal disease-related factors from research data base (NCBI, Bethesda MD USA). Results Sorting with the data base, we isolated a metabolic product, carnosine (beta-alanyl-L-histidine), which is abundant in young human blood samples and exerted a scavenger effects against the anti-oxidative stress. Carnosine is degraded by carnosinase encoded by CNDP1 gene, and its metabolism revealed renoprotective characterization including scavenger of reactive oxygens in various tissues. Furthermore, recent epidemiologic studies showed association between pathogenesis of diabetic nephropathy and CNDP1 gene polymorphism. Therefore, here we examined the levels of CNDP1 protein by Western blot analysis. CNDP1 protein was upregulated in ischemia-reperfusion kidneys significantly from old mice (52 weeks old), compared to those from young mice (6-8 weeks old) which showed little increased levels. The levels of CNDP1 protein were down-regulated by AM administration prior to ischemia-reperfusion in both old and young kidneys. These findings suggest that pharmacological effects of AM normalized carnosine metabolism by regulating expression of CNDP1, which plays a critical role in AKI pathogenesis of aged kidney. Conclusion AM administration can reduce day-to-day generated AKI by carnosine upregulation at least in part. The AM effects involved in carnosine metabolism would play a critical role in prolonging activity of aged kidney.