Diabetic Glomerulosclerosis
DN is the most common cause of progression of CKD to ESRD (1), as well as morbidity and mortality in patients with DM. DN is characterized early by glomerular hemodynamic abnormalities that will eventually lead to glomerular hyperfiltration and then to glomerular structural changes (see Fig. 2) (5-8). These changes progress to MAU and an eventual CKD and CVD if preventative measures are not taken.
Renal morphological changes in the initial stages involve hyperfiltration that is evidenced by glomerular basement thickening, mesangial extracellular matrix (ECM) expansion, and mesangial cell (MC) proliferation (5-8). A major pathology in diabetic glomerulosclerosis involves ECM deposition and MC expansion and proliferation leading to associated dysfunctional filtration (5). The abnormal filtration may be partly caused by an increase in the expression of growth factors and cytokines such as angiotensin (Ang)-II, aldosterone, tumor necrosis factor (TNF)-a, endothelin-1 (ET-1), interleukins (ILs), and vascular endothelial growth factor, all of which potentiate altered vascular flow and permeability (5). Increased expression of fibrotic factors such as transforming growth factor (TGF)-P, connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF) contribute to mesangial connective tissue deposition and expansion (5,6).
Progression of DN and associated atherosclerosis are affected by many common factors including intraglomerular and systemic HTN, hyperglycemia, dysfunctional and activation of the renin-angiotensin-aldosterone system (RAAS), and various growth and inflammatory factors (see Fig. 1). There are several pathways that have been implicated in the increased production of metabolic toxins or increased rective oxygen species (ROS) and include excessive formation of advanced glycation endproducts (AGE), activation of protein kinase C (PKC), increased metabolism through the polyol pathways (see Fig. 2) (5-19).
With hyperglycemia, there is an increased flux through the polyol pathway that converts glucose to fructose via two enzymes, aldose reductase and sorbitol dehydrogenase (7). These enzymes use a cofactor, nicotinamide adenine dinucleotide phosphate (NADPH) and NAD+, that when depleted, diminishes nitric oxide (NO) and vasodilatory prostaglandin production by endothelial cells (see Fig. 1). This may contribute to abnormal filtration and the associated increased NADPH/NAD+ ratio, which reduces glycolytic pathway signaling resulting in increased oxidative stress, increased production of PKC, increased de novo diacylglycerol synthesis, and AGE (5,8,9).
- Fig. 1. Common diabetic glomerular and vascular atherosclerotic changes.
The concentration of AGE is increased in many vascular and renal tissues and is thought to be a major culprit in diabetic CVD complications (10). Effects of AGE result from cell-surface binding to a receptor for AGEs (RAGE) and then subsequent accumulation in the ECM (11). The AGE-RAGE complex has been implicated in alteration of cellular signaling pathway and subsequent metabolic deregulation. These pathways include p28 (ras)-extracellular signal-regulated protein kinases (Erk1/2), Jac2/Stat3, and transcription nuclear factor (NF)-kP signaling pathways (12-14). This AGE-RAGE complex and its associated alteration of cell signaling has been shown to result in increased oxidative stress and activation of PKC and increased atherosclerosis and glomerulosclerosis (16,17). The vascular MC activation results then in increased cytokine and growth factors, the aforementioned TGF-B, VEGF, and platelet-derived growth factor (PDGF) secretion leading to further vascular remodeling and mesangial expansion (11-15).
Oxidative stress has been implicated as a major determinant in the CVD and renal complications of DM (see Figs. 1-3). This stress results from the imbalance of the generation of ROS (i.e., superoxide, hydrogen peroxide, and hydroxyl radical formation) and the reduced antioxidant mechanisms (i.e., superoxide dismutase, catalase, and glutathione peroxidase) (see Fig. 3) (19). When there is an imbalance (as in a state of insulin resistance, CKD, and HTN), the increased ROS alters basic cellular proteins causing cellular damage and reduced endothelial-derived NO (20). Many of the pathways for formation of ROS are interrelated and are driven, in part, by PKC activation and enhanced NADPH oxidase activity, xanthine oxidase, and uncoupled NO synthase (16,21).
NADPH oxidase as the main enzymatic source of ROS generation in MCs and vascular smooth muscle cells (VSMC), and markers of oxidative stress are activated in the diabetic rat glomeruli (21,22). ROS can also create increased expression of cell-signaling pathways
- Fig. 2. Pathways for diabetic vascular dysfunction.
via a second messenger (i.e., responses to Ang-II or PDGF) that will then lead to overexpression of cytokines including TGF-P, TNF-a, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, IL-1, 6, and 8, and ECM proteins such as collagen IV (23). Direct activation of NF-kP and activator protein 1 by ROS are likely to play an important role as well in vascular cellular changes (23).
The various PKC consitute a network of isoenzymes that act as intracellular signal transduction pathways for many hormones and cytokines. In diabetes, PKC activation may have effects on several intracellular signal transduction mechanism, including the previously mentioned Erk1/2, and NADPH oxidase (24). PKC activation has also been implicated in increasing the actions of several cytokines, such as VEGF, PDGF-B, CTGF, and ET-1 (25,26). Inhibition of PKC activity has shown to reduce elevated glomerular filtration rate (GFR), albuminuria, production of ECM proteins, expression of TGF-P, and CTGF, collagen deposition, and diabetic glomerulosclerosis (25-28). Induced PKC inhibitor treatment in a hypertensive, insulin-resistant rat model with overexpression of rat renin gene, inhibited mesangial expansion and reduced proteinuria (29,30). This would suggest that PKC inhibition could alter RAAS. In recent studies conducted in our laboratories, we have shown that increased tissue generation of ROS
Normal conditions
»Under normal conditions superoxide formation is converted safety into water and molecular oxygen 02, oxygen; e, electron; 02a, superoxide; H+, hydrogen; H202, hydrogen peroxide; CAT, catalase; H20, water.
Increased reactive oxygen species
*ln presence of excess superoxide, hydrogen peroxide can be converted to hydroxyl radicals, which are the most cytotoxic ROS known. As well, hydrogen peroxide can serve as a substrate for hypochlorous acid by myeloperoxidase, which is also a highly reactive ROS. H202, hydrogen peroxide; 02s, superoxide; MPO, myeloperoxidase; OH, hydroxyl radical; OH-, hydroxide; CI , chloride anion; hT, hydrogen cation; HOCL, hydrochlorous acid; H20, water.
Fig. 3. Formation of reactive oxygen species.
could also be corrected in this rodent model by angiotensin receptor-1 (ATjR) blockade and by administration of tempol, a superoxide dismutase-1 mimetic (29).
Post a comment