Nrf2 Activation Improves Mitochondrial Function in Kidneys of Aged F344 Rats
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Abstract:
Age is a major contributing factor for the development of many chronic pathologies including renal-cardiovascular and neurological disorders. People aged 65 years or above are at a high risk of developing kidney dysfunction. Aging is frequently associated with increased oxidative stress and impaired mitochondrial function. Studies have shown that the expression and function of Nrf2, a critical redox-sensitive transcription factor, is adversely affected during aging. However, the role of Nrf2 in the regulation of mitochondrial function in the aged kidney is not clear. Previous studies in our lab with Fischer 344(F344) rats have shown that mitochondrial respiration is impaired in the kidneys of aged rats along with decreased kidney function. The present study aimed to investigate the role of Nrf2 in the improvement of mitochondrial function in aged rat kidneys. Adult and aged Fischer 344 rats were kept on drinking water (control) or treated with sulforaphane, a potent activator of Nrf2, in drinking water. Treatment with sulforaphane significantly increased the Nrf2 expression in kidneys of aged rats compared to control aged rats. The level of Keap1, a repressor of Nrf2, was markedly increased in kidneys of aged rats which was significantly decreased by sulforaphane treatment. The treatment of adult rats with sulforaphane didn't show any increase in kidney Nrf2 expression compared with age-matched control rats. Nrf2 activation also significantly decreased the elevated levels of oxidative stress and increased the total antioxidant capacity in urine of aged rats compared to aged control. Glomerular damage indicators, proteinuria, and albuminuria, which were significantly high in aged rats were reduced by sulforaphane treatment. We found that antioxidant heme oxygenase 1(HO1) and mitochondrial transcription factor A (TFAM) were significantly reduced in the kidneys of aged rats. Nrf2 activation with sulforaphane improved the protein levels of both HO1 and TFAM. The impaired mitochondrial respiration was significantly improved by Nrf2 activation in renal cortical mitochondria of aged rats when compared to aged controls. Our study provides novel insights as it relates to the regulation of renal mitochondrial function by Nrf2 in aged rats and identifies cortical mitochondria-Nrf2 interaction as a therapeutic target to mitigate renal dysfunction in the aging population.Keywords:
Sulforaphane
KEAP1
Albuminuria
Albuminuria
Surrogate endpoint
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Albuminuria
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"Albuminuria" is an inadequate term; proteins other than albumin commonly appear in the urine. Proteinuria seems to depend upon failure of the tubules to reabsorb protein which has filtered through glomeruli. Its occurrence may be the result of abnormal plasma proteins, glomeruli or tubules. Proteinuria need not always be the result of a renal lesion, but may actually cause one. When proteinuria is discovered, it should arouse curiosity about the patient in general, not merely about his kidneys. Other clinical information is needed in order that treatment be directed appropriately.
Albuminuria
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Sulforaphane
KEAP1
Cytoprotection
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Ultraviolet radiation can not only induces acute and chronic inflammation in skin,but also trigger oxidative stress response tollowed by the production of reactive oxygen species (ROS).The Nrf2-Keapl system can counteract ROS via regulating the expression of protective genes in cells.As Nrf2 activators,natural antioxidants,such as (-)-epigallocatechin-3-gallate (EGCG),curcumin and sulforaphane counteract oxidative stress by directly scavenging free radicals or indirectly increasing endogenous cellular antioxidant defenses.In detail,these activators may activate Nrf2 by binding to Nrf2 or Keap1 with different chemical structures followed by alteration of configurations,which in turn initiates anti-oxidative stress response to counteract ultraviolet-induced oxidative stress.
Key words:
Nrf2 activator; Antioxidants; EGCG; Curcumin; Sulforaphane
Sulforaphane
KEAP1
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Albuminuria
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Sulforaphane
KEAP1
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ABSTRACT Chronic kidney disease (CKD) is defined according to a decrease in the glomerular filtration rate and kidney damage such as proteinuria or albuminuria. Dip‐stick proteinuria is only sensitive to albumin and correlates poorly with quantitative 24 h proteinuria, the most commonly used measure in renoprotective randomized controlled clinical trials (RCT). The amount of proteinuria correlates with the efficacy of angiotensin‐converting enzyme inhibitors in non‐diabetics in RCT. Random urine protein to creatinine ratio (PCR) or albumin to creatinine ratio (ACR) correlates with 24 h urinary excretion. Dip‐stick proteinuria correlates poorly with ACR, while PCR correlates reasonably well with ACR. Because of a high analytical variability, efforts are in progress to standardize ACR (but not PCR) measurement. There have been no studies on the direct comparison between proteinuria and albuminuria in terms of utilities (biomarker, surrogate end‐point and cost‐effectiveness). In this regard, both proteinuria and albuminuria are good biomarkers for cardiovascular events, renal events or mortality. However, there are limitations in RCT regarding the validity of proteinuria or albuminuria as a surrogate end‐point. In contrast, measuring proteinuria or albuminuria followed by treatment with angiotensin inhibitors is cost‐effective for diabetics, hypertension and aging. CKD guidelines differ in their opinions regarding the choice between ACR and PCR. Based on the current evidence, ACR might be recommended for the diabetics and PCR for the non‐diabetics.
Albuminuria
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Proteinuria and albuminuria are markers of kidney injury and function, serving as a screening test as well as a means of assessing the degree of kidney injury and risk for cardiovascular disease and death in both the diabetic and the non-diabetic general population.To evaluate the association between proteinuria below 300 mg/24 hours and albuminuria, as well as a possible association with kidney function in patients with diabetes mellitus (DM).The medical files of patients with type 1 and type 2 DM with proteinuria below 300 mg/24 hours at three different visits to the Diabetic Nephropathy Clinic were screened. This involved 245 patient files and 723 visits. The data collected included demographics; protein, albumin and creatinine levels in urine collections; blood biochemistry; and clinical and treatment data.The association between proteinuria and albuminuria is non-linear. However, proteinuria in the range of 162-300 mg/24 hours was found to be linearly and significantly correlated to albuminuria (P < 0.001, r = 0.58). Proteinuria cutoff, based on albuminuria cutoff of 30 mg/24 hours, was found to be 160.5 mg/24 hr. Body mass index (BMI) was the sole independent predictor of proteinuria above 160.5 mg/24 hr. Changes in albuminuria, but not proteinuria, were associated with changes in creatinine clearance.A new cutoff value of 160.5 mg/hr was set empirically, for the first time, for abnormal proteinuria in diabetic patients. It appears that proteinuria below 300 mg/24 hr is not sufficient as a sole prognostic factor for kidney failure.
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Urines of 6 normal subjects, collected during three consecutive 12-hour periods, were examined for proteinuria and albuminuria. During the first period, subjects were kept in the upright position, and during the next two periods in the recumbent position. Both position (upright and recumbent) and the urine collection period (day or night) significantly modify protein and albumin excretion. Proteinuria is more sensitive to different posture and albuminuria to different times of urine collection.
Albuminuria
Urine collection device
Microalbuminuria
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