Increased indoleamine 2,3-dioxygenase activity in type 2 diabetic nephropathy

doi:10.1016/j.jdiacomp.2016.08.020

Journal of Diabetes and its Complications

Volume 31, Issue 1, January 2017, Pages 223-227

https://doi.org/10.1016/j.jdiacomp.2016.08.020 Get rights and content

Abstract

Aim

The study aimed to test the hypothesis that indoleamine 2,3-dioxygenase (IDO) plays a pathogenic role in type 2 diabetic nephropathy (DN).

Methods

One hundred individuals were recruited in our study from January 2012 to December 2013, including group A (control group, 24 healthy adults), group B (20 patients with latent glomerulonephritis), group C (32 type 2 DN patients, estimated glomerular filtration rate (eGFR) > 30 ml/min per 1.73 m²), group D (24 maintenance hemodialysis, MHD patients). Clinical parameters such as gender, age, urine samples, serum creatinine, eGFR, L-tryptophan, L-kynurenine and 24 h urinary protein were collected and analyzed. Group C was further divided on C1 (eGFR > 60 ml/min per 1.73 m²) and C2 (eGFR 31–60 ml/min per 1.73 m²).

Results

Age was not related to IDO activity (r = 0.27, P = 0.057), while eGFR was significantly related to IDO activity (r = − 0.54, P = 0.002). IDO activity was significantly higher in the group C1 than group A (P = 0.003), group B (P = 0.008), and lower than in group D (P = 0.003).

Conclusions

IDO activity increased with severity of chronic kidney disease and negatively correlated with eGFR. Moreover, IDO activity was significantly increased in type 2 DN when eGFR was > 60 ml/min per 1.73 m², which suggested that IDO may closely correlate with the pathogenesis of type 2 DN.

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.

Section snippets

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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A fresh residual sera panel was collected from 80 healthy control (HC) individuals and 72 T2DM patients. Metabolites/ratios of interest including tryptophan (TRP), kynurenine (KYN), 5-hydroxytryptamine (5HT), kynurenic acid (KA), xanthurenic acid (XA), neopterin (NEO), KA/KYN ratio and KYN/TRP ratio were determined using a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics approach, and the difference between groups was assessed. Supervised orthogonal partial least squares-discriminant analysis and differential metabolite screening with fold change (FC) were performed to identify distinct biomarkers. The diagnostic performance of KP metabolites in T2DM was evaluated.
Significant decreases of TRP, 5HT, KA, XA, and KA/KYN and increases of KYN/TRP and NEO in T2DM compared to HC group were observed (P < 0.05). The KP metabolites panel significantly changed between T2DM and HC groups (Q²: 0.925, P < 0.005). 5HT (FC: 0.63, P < 0.01) and NEO (FC: 3.27, P < 0.01) were proven to be distinct differential metabolites. A combined testing of fasting plasma glucose and KYN/TRP showed good value in the prediction of T2DM (AUC: 0.904, 95% CI 0.843–0.947).
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In recent years, the incidence rate of diabetes mellitus (DM), including type 1 diabetes mellitus(T1DM), type 2 diabetes mellitus(T2DM), and gestational diabetes mellitus (GDM), has increased year by year and has become a major global health problem. DM can lead to serious complications of macrovascular and microvascular. Tryptophan (Trp) is an essential amino acid for the human body. Trp is metabolized in the body through the indole pathway, kynurenine (Kyn) pathway and serotonin (5-HT) pathway, and is regulated by intestinal microorganisms to varying degrees. These three metabolic pathways have extensive regulatory effects on the immune, endocrine, neural, and energy metabolism systems of the body, and are related to the physiological and pathological processes of various diseases. The key enzymes and metabolites in the Trp metabolic pathway are also deeply involved in the pathogenesis of DM, playing an important role in pancreatic function, insulin resistance (IR), intestinal barrier, and angiogenesis. In DM and its complications, there is a disruption of Trp metabolic balance. Several therapy approaches for DM and complications have been proven to modify tryptophan metabolism. The metabolism of Trp is becoming a new area of focus for DM prevention and care. This paper reviews the impact of the three metabolic pathways of Trp on the pathogenesis of DM and the alterations in Trp metabolism in these diseases, expecting to provide entry points for the treatment of DM and its complications.
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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.

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Increased indoleamine 2,3-dioxygenase activity in type 2 diabetic nephropathy

Abstract

Aim

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Clinical characteristics analysis

Discussion

Experimental and Molecular Pathology

Vaccine

The Lancet

Trends in Endocrinology & Metabolism

Immunity

Diabetes Research and Clinical Practice

Function of indoleamine 2, 3-dioxygenase in corneal allograft rejection and prolongation of allograft survival by over-expression

European Journal of Immunology

Changes in plasma kynurenic acid concentration in septic shock patients undergoing continuous veno-venous haemofiltration

Inflammation

Combined angiotensin inhibition for the treatment of diabetic nephropathy

New England Journal of Medicine