Increased indoleamine 2,3-dioxygenase activity in type 2 diabetic nephropathy
Introduction
DN is a leading cause of end-stage renal failure worldwide (Marchant et al., 2015), and its pathogenesis is multifactorial (Wada & Makino, 2013). The intensified multifactorial intervention resulted in reduced risk of cardiovascular events and mortality, and reduced risk of DN development and progression in the Steno 2 trial (Gæde, Lund-Andersen, Parving, & Pedersen, 2008). However, the incidence of DN is progressively increasing worldwide (Gæde et al., 1999, Ravid et al., 1993). It is still important to elucidate the pathogenesis for therapy and prevention of DN due to the pathogenesis remained unclear recently.
IDO is a rate-limiting enzyme in tryptophan catabolism pathway (Schefold et al., 2009). IDO itself has been demonstrated as a key player in immunologic processes, including infection, autoimmunity, allergic reaction, chronic inflammation and renal injury (Beutelspacher et al., 2006, Mohib et al., 2008, Puccetti and Grohmann, 2007). Moreover, IDO expression has been shown to be induced by inflammatory stimuli (O'Connor et al., 2009).
To date, although there are studies that claimed up-regulation of IDO activity in type 2 DN patients likely reflects activation of compensatory mechanisms to curtail inflammation and cell injury (Baban, Liu, & Mozaffari, 2013), the studies of IDO have focused on type 1 DN and the relevance of IDO with type 2 DN gets less attentions.
In the present study, we hypothesized that IDO may play role in the pathogenesis of type 2 DN. IDO activity in type 2 DN patients and correlation of parameters related to IDO activity were analyzed.
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Study population
This prospective study was approved by the ethics committee of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, performed in accordance with the Declaration of Helsinki, and written informed consent was obtained from all patients and their families before enrollment. In our study, 100 individuals were recruited from January 2012 to December 2013. All individuals were first divided into four groups, including group A (control group, 24 healthy people), group B (20
Clinical characteristics analysis
Baseline demographic and clinical data for all 4 groups were shown in Table 1. As shown, most of individuals recruited were female with mean age 41.5 (17–64) years. Proteinuria presented in 93.8% of DN patients and hematuria in 31.3%.
The four groups showed significant difference levels in eGFR (F = 35.01, P = 0.000), L-tryptophan (F = 12.00, P = 0.000), L-kynurenine (F = 17.82, P = 0.000) and IDO activity (F = 90.16, P = 0.000). There were no differences in eGFR between group A and group B (P > 0.05), but eGFR
Discussion
In the present study, we focused on IDO activity in patients of type 2 DN when eGFR was > 60 ml/min per 1.73 m2. Here, we hypothesized that IDO might play a role in the pathogenesis of type 2 DN.
As a heme enzyme in cytoplasm, IDO is widely expressed in extrahepatic tissues in mammals. IDO might be regulated by inflammation and endoplasmic reticulum stress (ERS), thus involved in the pathogenesis of type 2 DN (Baban et al., 2013). Activity of IDO and ERS in renal tissue was significantly increased
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Abnormal tryptophan catabolism in diabetes mellitus and its complications: Opportunities and challenges
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2020, Advances in Clinical ChemistryCitation Excerpt :Plasma TRP is inversely associated with CVD incidence [228]. In contrast, increased IDO-1 activity and KYN were positively associated with low-grade inflammation, obesity, dyslipidemia, insulin resistance and diabetes [226,229–231]. Downstream TRP metabolites along both 5-HT and KYN pathways may be associated with cardiovascular events due to their direct effect on the vasculature [232–234].
Metabolomic study of the protective effect of Gandi capsule for diabetic nephropathy
2019, Chemico-Biological InteractionsCitation Excerpt :Another explanation was that the decreased levels of tryptophan may be due to the increase activity of indoleamine 2,3-dioxygenase (a rate-limiting enzyme in tryptophan catabolism), which was reported to be closely correlate with the pathogenesis of DN [23]. In the meantime, our findings of decreased concentration of tryptophan and increased levels of oxidation metabolites of tryptophan were consistent with the previous studies [21,23,24]. In DN + GDC group, l-tryptophan and indole-3-carboxylic acid were significantly reversed to normal level, meanwhile, the other two were also reversed at different extent, which suggested that retrieving tryptophan metabolism may play an important role in GDC's protective effects.
Circulating metabolites improve the prediction of renal impairment in patients with type 2 diabetes
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Funding: This study was funded by Sichuan Provincial Health Department (no. 130169) and by Dr. Foundation of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (no. 30305030592).
Declaration of interest: The authors report no conflicts of interest.