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.
Forty two, six month old, albino wistar rats were randomly divided into seven groups. All groups except group I which served as control were given cadmium chloride @100mg/L of drinking water. Silymarin @100mg/kg bwt in group III and EVBP and SPBP @ 1 and 2% in groups IV, V, VI and VII, respectively were given in feed for 90 days. After 90 days, the histopathological changes were characterized by vascular and inflammatory changes in kidneys, liver, lungs, heart and brain. Histopathological changes were severe in only Cd treated rats while mild to moderate changes were found in EVBP and SPBP treatment groups. On electron microscopy, ultra structure of the renal and hepatic cells showing disappearance of nucleolus, pyknosis and marginalisation of chromatin material at the periphery of the nucleus were evident in the group II. It is concluded from the present study that the bark powder of E. variegata and Spondia spinnata have ameliorative effect on tissues of these organs in cadmium chloride induced toxicity in rats.
Recently we have shown that activation and formation of NLRP3 inflammasomes in podocytes is implicated in the development of obesity‐induced glomerular injury. Moreover, we demonstrated that NADPH oxidase dependent O 2 •− production (ROS) mediates the obesity‐induced NLRP3 inflammasomes activation and thereby results in podocyte injury and glomerular damage. However, it remains unknown how NADPH oxidase‐derived ROS is sensed by NLRP3 inflammasomes in podocytes upon visfatin stimulation. The current study tested whether thioredoxin‐interacting protein (TXNIP) mediates obesity‐induced NLRP3 inflammasome activation and consequent glomerular injury. In cultured podocytes, confocal microscopic analysis showed that visfatin treatment significantly increased the colocalization of NLRP3 with Asc or caspase‐1 in podocytes compared to control cells. Pretreatment with TXNIP siRNA abolished the visfatin‐induced inflammasome formation. Correspondingly, visfatin treatment significantly increased the caspase‐1 activity and IL‐1β production compared to control cells. The TXNIP siRNA transfection significantly attenuated the visfatin‐induced caspase‐1 activity and IL‐1β production. Further immunofluorescence analysis showed that visfatin treatment significantly decreased the podocin expression (podocyte damage) compared to control cells. However, pretreatment with TXNIP siRNA attenuated the visfatin‐induced podocin reduction. In in vivo studies, adult C57BL/6J male mice were fed a high fat diet for 14 weeks to induce obesity, and TXNIP was inhibited by verapamil (1 mg/ml in drinking water). High fat diet significantly increased the plasma visfatin levels compared to control mice. In addition, RT‐PCR analysis showed that high fat diet significantly increased the Nlrp3 expression in glomeruli of wild type mice compared to control mice but not in verapamil treated mice. Furthermore, TXNIP inhibition significantly reduced IL‐1β production in glomeruli of mice with obesity. Correspondingly, TXNIP inhibitor, verapamil attenuated obesity‐induced proteinuria, glomerular damage and podocyte injury. In conclusion, our results demonstrate that TXNIP binding to NLRP3 is a key signaling mechanism necessary for obesity‐induced NLRP3 inflammasome formation and activation and subsequent glomerular injury Support or Funding Information NIH grant, DK104031 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Aging has a strong association with the development of kidney disease. About one in four women and one in five men, aged 65 years and above, have chronic kidney disease (CKD). Studies indicate compromised mitochondrial function in aging kidneys. However, the mechanisms of the decreased mitochondrial function in aging is unclear. The present study aims to investigate the mechanisms relating to the mitochondrial dysfunction in aging. The mechanisms thus explored will help us identify novel therapeutic targets to prevent or reverse kidney damage in elder individuals. Nuclear transcription factor Nrf2 is a cytosolic protein which when activated will translocate to the nucleus. After being translocated to the nucleus, it regulates the expression of genes involved in antioxidant and detoxification mechanisms. It binds to Antioxidant Response Element (ARE) on the gene promoters and increases the expression of genes that regulate the function of cells. We previously showed that Nrf2, was decreased in the kidneys of aged rats. Additionally, we also found a decrease in mitochondrial activity and kidney function. Therefore, we hypothesized that Nrf2 regulates kidney function via improving mitochondrial function during aging. We tested this hypothesis, by using Fischer344 rats, animal model of aging, and human kidney cells (HK2) in culture. Aged male Fischer 344 (F344) rats (20–24 months old) were divided into two groups. One group was treated with Nrf2 activator, sulforaphane (SF) [15mg/kg/day in drinking water for four weeks] and the other group (Control) was given drinking water alone. Nrf2 activation had significantly reduced the oxidative stress marker 8‐isoprostane levels in urine and increased urinary antioxidant capacity in the aged rats compared to their controls. The increased levels of protein in urine and plasma creatinine in aged animals were also reduced by sulforaphane treatment. Human kidney cells (HK2) were treated with sulforaphane (SF) at a dose of 20uM in the presence and absence of H 2 O 2 . H 2 O 2 treatment significantly reduced Nrf2 expression which was reversed by SF treatment. Also, the mitochondrial membrane potential improved in H 2 O 2 +SF treated cells as compared to H 2 O 2 treated cells. In conclusion, our results suggest that Nrf2 activation plays a key role in improving kidney function in aged rats. Support or Funding Information NIH Aging grant: AG057024‐01A1
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