Modulation of the Cellular Expression of Circulating Advanced Glycation End-Product Receptors in Type 2 Diabetic Nephropathy

Karly C Sourris,Brooke E Harcourt,Michael J Davies,Scott T Baker,Josephine M Forbes,Felicia Y T Yap,Sally A Penfold,George Jerums,Philip E Morgan,Amy L Morley

doi:10.1155/2010/974681

Abstract

Background. Advanced glycation end-products (AGEs) and their receptors are prominent contributors to diabetic kidney disease. Methods. Flow cytometry was used to measure the predictive capacity for kidney impairment of the AGE receptors RAGE, AGE-R1, and AGE-R3 on peripheral blood mononuclear cells (PBMCs) in experimental models of type 2 diabetes (T2DM) fed varied AGE containing diets and in obese type 2 diabetic and control human subjects. Results. Diets high in AGE content fed to diabetic mice decreased cell surface RAGE on PBMCs and in type 2 diabetic patients with renal impairment (RI). All diabetic mice had elevated Albumin excretion rates (AERs), and high AGE fed dbdb mice had declining Glomerular filtration rate (GFR). Cell surface AGE-R1 expression was also decreased by high AGE diets and with diabetes in dbdb mice and in humans with RI. PBMC expression of AGE R3 was decreased in diabetic dbdb mice or with a low AGE diet. Conclusions. The most predictive PBMC profile for renal disease associated with T2DM was an increase in the cell surface expression of AGE-R1, in the context of a decrease in membranous RAGE expression in humans, which warrants further investigation as a biomarker for progressive DN in larger patient cohorts.

Highlights

Advanced glycation end products (AGEs) are a heterogeneous and complex group of biochemical modifications, which play an important role in the development of chronic disease processes including the complications of diabetes [1]
Flow cytometry was used to measure the predictive capacity for kidney impairment of the Advanced glycation end-products (AGEs) receptors RAGE, AGE-R1, and AGE-R3 on peripheral blood mononuclear cells (PBMCs) in experimental models of type 2 diabetes (T2DM) fed varied AGE containing diets and in obese type 2 diabetic and control human subjects
Analysis of the low and high AGE diets administered to these mice revealed that the CML content was 90 or 370 nmoles CML per mole of serine, respectively

Summary

Introduction

Advanced glycation end products (AGEs) are a heterogeneous and complex group of biochemical modifications, which play an important role in the development of chronic disease processes including the complications of diabetes [1]. The receptor for advanced glycation end products, RAGE, is a transmembrane receptor, expressed on the cell surface of a number of circulating and organ-specific cells including monocytes, macrophages, proximal tubular cells, podocytes, and mesangial cells [4,5,6]. Diets high in AGE content fed to diabetic mice decreased cell surface RAGE on PBMCs and in type 2 diabetic patients with renal impairment (RI). Cell surface AGE-R1 expression was decreased by high AGE diets and with diabetes in dbdb mice and in humans with RI. The most predictive PBMC profile for renal disease associated with T2DM was an increase in the cell surface expression of AGE-R1, in the context of a decrease in membranous RAGE expression in humans, which warrants further investigation as a biomarker for progressive DN in larger patient cohorts

Methods

Results

Conclusion