Exposure of renal cells to high glucose (HG) during diabetes has been recently proposed to be involved in renal injury. In the present study, we investigated a potential mechanism by which AICAR treatment regulates the DNA repair enzyme, 8-oxoG-DNA glycosylase (OGG1) in renal proximal tubular mouse cells exposed to HG and in kidney of db/db mice. Cells treated with HG for 2 days show inhibition in OGG1 promoter activity as well as OGG1 and Nrf2 protein expression. In addition, activation of AMPK by AICAR resulted in an increase raptor phosphorylation at Ser and leads to increase the promoter activity of OGG1 through upregulation of Nrf2. Downregulation of AMPK by DN-AMPK and raptor and Nrf2 by siRNA resulted in significant decease in promoter activity and protein expression of OGG1. On the other hand, downregulation of Akt by DN-Akt and rictor by siRNA resulted in significant increase in promoter activity and protein expression of Nrf2 and OGG1. Moreover, gel shift analysis shows reduction of Nrf2 binding to OGG1 promoter in cells treated with HG while cells treated with AICAR reversed the effect of HG. Furthermore, db/db mice treated with AICAR show significant increased in AMPK and raptor phosphroylation as well as OGG1 and Nrf2 protein expression that associated with significant decrease in oxidative DNA damage (8-oxodG) compared to non-treated mice. In summary, our data provide a novel protective mechanism by which AICAR prevents renal cell damage in diabetes and the consequence complications of hyperglycemia with a specific focus on nephropathy.
The tuberous sclerosis complex (TSC) is caused by mutation in either of 2 tumor suppressor genes, TSC-1 (encodes hamartin) and TSC-2 (encodes tuberin). In humans, deficiency in TSC1/2 is associated with benign tumors in many organs, including renal angiomyolipoma (AML) but rarely renal cell carcinoma (RCC). In contrast, deficiency of TSC function in the Eker rat is associated with RCC. Here, we have investigated the activity of PI 3-K and the expression of PTEN, p53, tuberin, p-mTOR, and p-p70S6K in both Eker rat RCC and human renal AML. Compared to normal tissue, increased PI 3-K activity was detected in RCC of Eker rats but not in human AML tissue. In contrast, PTEN was highly expressed in AML but significantly reduced in the renal tumors of Eker rats. Phosphorylation on Ser 2448 of mTOR and Thr 389 of p70S6K were significantly increased in both RCC and AML compared to matching control tissue. Total tuberin was significantly decreased in AML while completely lost in RCC of Eker rats. Our data also show that while p53 protein expression is lost in rat RCC, it was highly elevated in AML. These novel data provide evidence that loss of TSC-2, PTEN, and p53 as well as activation of PI 3-K and mTOR is associated with kidney cancer in the Eker rat, while sustained expression of TSC-2, PTEN, and p53 may prevent progression of kidney cancer in TSC patients.
Introduction: Mandagni has been considered one of the primary indigenous factors for the manifestation of Amavata, so there might be the effect of the causative factors affecting the status of Agnibala of an individual. Hence an attempt can be made to observe the status of Agnibala and Koshta with particular reference to different inflammatory markers present in subjects of Aamvata. Material and Method: The main goal of the study was to evaluate the Agnibala and Koshtha of the Amavata Patients and to determine the relationship between Agni and Koshtha with the inflammatory parameters of Rheumatoid Arthritis as the characteristics of Amavata are similar to Rheumatoid Arthritis. The aims and Objectives of the study include the Assessment of Koshtha using a self-developed Standard Proforma for Koshtha Assessment (KAQ). Agnibala, using a standard proforma developed by Singh A et al., 2016. Amavata patients were encouraged to undertake Haematological examinations along with Investigations of Inflammatory markers of Rheumatoid arthritis and their reports were collected and analysed for additional statistical analysis. BHU's CCI lab and other standard laboratories were used for the research. The data were then statistically analysed. Results and Conclusion: According to the Agni Bala assessment from this study, it can be said that Mandagni is the main causative factor for the development of Amavata. A good correlation has been found between symptoms of Amavata and ACR criteria of Rheumatoid Arthritis from this study. A significant association was found between Madhyam Koshtha and Amavata as provocative factors. There is also a significant correlation found between Koshtha and Agni.
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