Pathogenesis of diabetic nephropathy: a radical approach.

Abstract

factors, extracellular matrix (ECM ) proteins and Introduction inflammatory cytokines, as well as to stimulate cell proliferation [8,9]. AGEs have also been shown to Diabetes is on the rise and diabetic kidney disease has quench nitric oxide, and have been implicated in the emerged as a leading cause for end-stage renal failure pathogenesis of atherosclerosis [11,12]. The cellular in certain parts of the world [1]. Although data from and molecular mechanisms responsible for AGE-medithe Diabetes Control and Complication Trial establish ated cellular effects have not yet been fully defined. a central role for hyperglycaemia in diabetic complicaRecent studies suggest that a central pathway through tions [2], strict control of glucose in diabetics can be which AGEs mediate their cellular effects may involve difficult, and some times dangerous. Understanding the interaction of AGEs with their cellular binding the distal pathway of glucose toxicity therefore has sites, the best characterized is the Receptor for AGE clinical significance. Although during chronic hyper(RAGE ) [13,14]. glycaemia multiple glucose metabolites and reaction products accumulate, accruing evidence supports a key role for advanced glycation end-products (AGEs) in diabetic complications [3–10]. There are several theorAGE–RAGE interaction etical reasons and experimental evidence that suggest an important role for AGEs and oxidative stress in RAGE is expressed on a number of cell types that are the pathogenesis of diabetic nephropathy. relevant to the pathogenesis of diabetic complications. These include endothelial, mesangial and vascular smooth muscle cells and macrophages [15]. Based on AGEs in diabetic nephropathy preliminary reports, the activation of NF-kB by AGEs appears to be mediated through a signalling mechanism AGEs are formed from the non-enzymatic glycation/ involving p21ras and MAP kinase [16]. AGE–RAGE oxidation not only of amino acids of proteins, but also interactions may be a potential pathway for the extraof lipids and lipoproteins [11,12]. In patients with cellular protein gene activation during diabetes based diabetic nephropathy, high levels of AGEs accumulate on the following observation. AGE albumin when in the plasma, and importantly, within the sclerosing perfused in situ interacted with vascular wall, via glomeruli [3,4]. The latter has been noted to precede binding to RAGE. AGE–RAGE interaction was the onset of diabetic renal disease, and correlate with accompanied by activation of IL-6 and VCAM-1 genes the course of the disease [10]. In animals, chronic [17,18]; the latter may explain the elevated plasma administration of advanced glycated albumin to nonsoluble VCAM-1 (sVCAM ) reported in human diadiabetic rats led to proteinuria and glomerular changes betics [19]. Such upregulation of VCAM-1 expression, similar to those seen in diabetic nephropathy, and in theory, can contribute to the diabetic vascular these changes were associated with activation of lesions, since VCAM-1 is a cell–cell recognition protein collagen, laminin, and TGF-b genes [9,11]. on the endothelial cell surface, which promotes interTissue accumulation of AGEs is associated with a action between circulating monocytes and endothelnumber of toxic effects. These include cross-linking of ium. long-lived proteins such as collagens and other matrix Since many effects of AGEs such as cross-linking of proteins, increasing of vascular permeability, and proproteins, increased vascular permeability, induction of motion of mononuclear cell influx [8,9]. Additionally lipid peroxidation, quenching of nitric oxide, and accelAGEs have been shown to induce genes for growth eration of atherosclerosis can also be duplicated by the effects of free radicals, attention has recently been Correspondence and offprint requests to: Abdulla K. Salahudeen MD focused on examining whether AGE–RAGE interFRCP, Renal Division, Department of Medicine, University of action can indeed lead to increased free radical Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216–4505, USA. production.