Oxidative Stress Induced Diabetic Nephropathy

 

Vadivelan R«, Umasankar P, Dipanjan Mandal, Shanish A, Dhanabal S.P and Elango K

Department of Pharmacology, J.S.S College of Pharmacy, (Off campus of JSS University, Mysore) Ooty, Niligiris-643001

ABSTRACT:

Diabetic nephropathy is one of the main causes of renal end-stage disease. Morphologically, the development of diabetic nephropathy is characterized by progressive thickening of the glomerular basement membrane and by expansion of the mesangial matrix which correlates to glomerular filtration function. Hyperglycemia generates more reactive oxygen species and also attenuates antioxidative mechanisms through glycation of the scavenging enzymes. Therefore, oxidative stress has been considered to be a common pathogenetic factor of the diabetic complications including nephropathy. A causal relationship between oxidative stress and diabetic nephropathy has been established by observations that (1) Lipid peroxides and 8-hydroxydeoxyguanosine, indices of oxidative tissue injury, were increased in the kidneys of diabetic rats with albuminuria.(2) High glucose directly increases oxidative stress in glomerular mesangial cells, a target cell of diabetic nephropathy.(3) oxidative stress induces mRNA expression of TGF-b1(transforming growth factor beta1) and fibronectin which are the genes implicated in diabetic glomerular injury, and (4) Inhibition of oxidative stress ameliorates all the manifestations associated with diabetic nephropathy.

 

KEYWORDS: Diabetic nephropathy; Extracellular matrix; High glucose; Oxidative stress.

 

INTRODUCTION:

Diabetic nephropathy is kidney disease or damage that results as a complication of diabetes. The exact cause of diabetic nephropathy is unknown, but it is believed that uncontrolled high blood sugar leads to the development of kidney damage, especially when high blood pressure is also present. In some cases, your genes or family history may also play a role. Not all persons with diabetes develop this condition. Each kidney is made of hundreds of thousands of filtering units called nephrons. Each nephron has a cluster of tiny blood vessels called a glomerulus. Together these structures help remove waste from the body. Too much blood sugar can damage these structures, causing them to thicken and become scarred. Slowly, over time, more and more blood vessels are destroyed. The kidney structures begin to leak and protein (albumin) begins to pass into the urine1. Diabetes mellitus refers to a number of disorders characterized by chronic hyperglycaemia and alterations of cellular homeostasis, which lead to diffuse vascular damage and multiorgan dysfunction2.

 

OXIDATIVE STRESS AND RENAL INJURY:

The global term reactive oxygen species (ROS) includes both oxygen radicals such as superoxide (O2._), alkoxyl (RO.), peroxyl (ROO.), and hydroxyl radicals (OH.), plus non-radical derivatives of oxygen, namely hydrogen peroxide (H2O2) and ozone (O3). When the generation of ROS exceeds cellular defence power, these unstable ROS will interact with essential biological cellular macromolecules such as lipids, proteins, and


 

 

DNA which leads to histologic changes as well as functional abnormalities. The shift of balance between prooxidant and antioxidant activity in favour of the former, which results in potential damage, is defined as oxidative stress3. Numerous studies on experimental models of both immune and nonimmune glomerular injury demonstrated ROS to be primary mediators in the pathogenesis of these disorders and showed that the kidney is in fact, susceptible to oxidative stress4-8.  (Fig-1)

 

Hyperglycemia-Induced Oxidative Stress in Diabetic Nephropathy:

Hyperglycemia, a well recognized pathogenetic factor of long-term complications in diabetes mellitus 9, 10 not only generates more ROS but also attenuates antioxidative mechanisms through glycation of the scavenging enzymes. Therefore, oxidative stress has been considered to be a common pathogenic factor of diabetic complications including nephropathy 11-14. In order to establish a role for oxidative stress in diabetic nephropathy, it has to be demonstrated that

(1) Oxidative stress is increased in the diabetic kidney preferably before clinical    signs of nephropathy;

(2) High glucose can increase oxidative stress in target cells in vitro,

(3) Oxidative stress has a relevant effect on target cells in vivo and in vitro, and

(4) Inhibition of oxidative stress in vivo as well as in vitro blocks the manifestations of the disease.15

 

Mechanisms Involved In High Glucose-Induced Oxidative Stress in Diabetic Nephropathy:

One of the major biochemical pathways inducing diabetic nephropathy is the activation of diacylglycerol (DAG)-PKC16. PKC(protein kinase C) is activated in the glomeruli of diabetic rats17 Activation of PKC has a modulatory role in oxidative stress-induced glomerular injury18–21 .We observed phorbol ester, a PKC activator, increased TGF-b1 and fibronectin mRNA expression by mesangial cells in a preliminary study22. Furthermore, inhibition of PKC activity effectively blocked high glucose- and H2O2-induced TGF-b1 and fibronectin mRNA expression as well as phorbol ester-induced TGF-b1 and fibronectin mRNA expression in mesangial cells. This study clearly demonstrated the relationship between PKC and oxidative stress under hyperglycemia.

 

While further studies are necessary to gain a better understanding of the precise role of glucose autooxidation, the formation of advanced glycosylation end products (AGE), and metabolic stress resulting from oxidative stress associated with hyperglycemia, AGE is accepted as an independent risk factor for diabetic nephropathy23-25 AGE interaction with its cognate receptors is also a potential source for oxidative stress in diabetes26,27 and AGE-induced oxidative stress has been proposed to play a major role in the development and progression of diabetic  nephropathy28. Since glycated low density lipoprotein- induced fibronectin mRNA expression and protein synthesis by mesangial cells is, in part, mediated by PKC activation29 PKC may also have a modulatory role in oxidative stress involved in AGE-induced extracellular expansion.

 

Thus, it can be summarized that oxidative stress associated with hyperglycemia plays an important part in the development and progression of diabetic nephropathy. Understanding the mechanisms involved in oxidative stress associated with hyperglycemia should help delineate the pathogenesis of diabetic nephropathy further.

 

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Received on 10.07.2010

Accepted on 02.08.2010     

© A&V Publication all right reserved

Research J. Pharmacology and Pharmacodynamics. 2(5): Sept.-Oct. 2010, 321-323