Receptor for AGEs (RAGE) blockade may exert its renoprotective effects in patients with diabetic nephropathy via induction of the angiotensin II type 2 (AT2) receptor

Abstract

Aims The receptor for advanced glycation end products (RAGE) contributes to the development and progression of diabetic nephropathy. In this study, we examined if the protective effects afforded by RAGE blockade are via modulation of the renal AT-2 receptor. Methods Control and streptozotocin diabetic mice, wild type (WT) or deficient in either the angiotensin II type 2 receptor (AT-2 KO) or RAGE (RAGE KO), were studied for 24 weeks. Albumin excretion rate (AER), creatinine clearance (CrCl), renal cortical RAS components and RAGE expression were assessed. Results With diabetes, RAGE deficient mice had lower AER and attenuation of hyperfiltration, as compared with both diabetic WT and AT-2 deficient mice. Gene expression of RAGE was elevated in diabetic kidneys, while elevations in renal membranous RAGE expression were evident in WT and AT-2 KO mice with diabetes. Diabetic RAGE KO mice had an amelioration of diabetes induced increases in renal AT-2 gene expression. Although renal AT-2 protein expression was increased by diabetes in WT mice, it was further elevated in diabetic RAGE KO mice. Diabetes-induced increases in renal superoxide, were prevented in diabetic RAGE KO but not diabetic AT-2 KO mice. Adenoviral overexpression of RAGE or AGE treatment, decreased cell surface AT-2 expression, resulting in superoxide generation which was reversed by apocynin in primary mesangial cells. Conclusions We postulate that RAGE appears to be a common and key modulator of AT-2 receptor expression, which implicates a newly defined RAGE/AT-2 axis in the development and progression of diabetic nephropathy.

Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes

“…There Cortical HMGB-1 (ng/mg protein) was evidence of reconstitution of glomerular cells by bone marrow from both donor groups as has been previously shown in diabetes [24], but the relative contribution of these remains to be delineated in future studies. Global RAGE deficiency has been shown to provide protection against renal injury in experimental models of diabetes [9,10]. However, these studies were not able to determine if the deletion of RAGE on infiltrating cells per se was responsible for the improved renal function and structure as identified in the present study.…”

“…; MP Biomedicals, Eschwege, Germany) or vehicle (sodium citrate buffer, pH 4.5) for 5 consecutive days as previously described [9,10]. Throughout the duration of the study, mice were given standard mouse chow and water ad libitum while kept on a 12 h day/night cycle.…”

“…Glycated haemoglobin (GHb) was measured in whole blood by HPLC (CLC330 GHb Analyser; Primus, Kansas City, MO, USA) as previously described [9,10].…”

“…Serum S100A8/9 (Immundiagnostik) as well as plasma mouse macrophage-colony stimulating factor (M-CSF; R&D Systems), were assayed by ELISA according to the manufacturer's instructions. Urinary and plasma AGE-modified (carboxymethyllysine [CML]) albumin were assayed via ELISA as previously described [9].…”

“…Studies in experimental animal models of diabetes have identified a functional role for both macrophages and the receptor for AGEs (RAGE) in the pathogenesis of diabetic nephropathy [8][9][10][11]. RAGE is expressed on macrophages and other circulating and resident tissue cells, and has a physiological role in antigen presentation, dendritic cell homing to lymph nodes and T cell priming [12].…”