New Mechanistic Insights in the Development of Diabetic Nephropathy: Role of Cytochromes P450 and Their Metabolites

Review Article

J Endocr Disord. 2014;1(1): 1006.

New Mechanistic Insights in the Development of Diabetic Nephropathy: Role of Cytochromes P450 and Their Metabolites

Stephanie Eid, Cesar Abdul-Massih, Christopher M El-Khuri, Ahmed Hamdy2, Awad Rashid2 and Assaad A Eid1*

1Department of Anatomy Cell Biology and Physiology, American University, Lebanon

2Department of Nephrology, Hamad Medical Corporation, Qatar

3The Authors Equally Contributed to This Work.

*Corresponding author: Assaad A. Eid, Faculty of Medicine, Department of Anatomy, Cell Biology and Physiology, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Lebanon

Received: Aug 08, 2014; Accepted: Aug 27, 2014; Published: Aug 28, 2014


Diabetic Nephropathy (DN), a major complication of diabetes, is characterized by hypertrophy, extracellular matrix accumulation, fibrosis and proteinuria leading to loss of renal function. However, the mechanisms leading to kidney injury is not well defined. Arachidonic acid is primarily metabolized by Cytochromep-450 (CYP) enzymes to 20-Hydroxyeicosatetraenoic acid (20-HETE) and Epoxyeicosatrienoic acids (EETs) and these compounds have a role in renal physiology and pathophysiology. Recent studies show that the production of EETs and 20-HETE is altered in diabetes. More interestingly, we and others have established a link between the alteration in the production of 20-HETE and EETs and the onset and development of diabetic-induced kidney injury, and that these cytochromes P450 metabolites of arachidonic acid contribute to the changes in renal structure and function seen in diabetic nephropathy. All the results described in this review suggest that the drugs that modify the formation and/or actions of EETs and 20-HETE may have therapeutic benefits for diabetic nephropathy treatment.

Keywords: Diabetic Nephropathy; Reactive Oxygen Species (ROS); Cytochromes P450; 20-HETE; EETs

Diabetes-related Kidney Disease or Diabetic Nephropathy

Diabetes is a major public health problem that affects about 8% of the world population. An estimated 24.1 million people have diabetes [1]. The incidence of diabetes has increased tremendously in the past 10 years. This alone makes it an epidemic disease. Diabetes is associated with a number of metabolic risk factors that contribute to a high rate of micro and macro vascular events.

Diabetes-related kidney disease or Diabetic Nephropathy (DN) is a major risk factor for cardiovascular morbidity and mortality and is considered to be one of the most serious complications of diabetes worldwide, affecting up to 25% and 40% of all patients with type 1 and type 2 diabetes, respectively [2]. DN is characterized by increased urinary albumin excretion (microalbuminuria), which often progresses to proteinuria, one of the most important prognostic risk factors for kidney disease progression [3]. Microalbuminuria/ proteinuria develops as a consequence of a series of structural changes in the vascular, glomerular, tubular and interstitial compartments in the absence of measurable dysfunction [4].

The glomerular changes include hyperplasia/hypertrophy with thickening of glomerular basement membrane, mesangial expansion with extracellular matrix accumulation, changes in glomerular epithelial cells (podocytes), including a decrease in number and/ or density, podocyte foot process broadening and effacement and glomerulosclerosis. Similar changes occur in the tubulointerstitial compartment and include matrix protein accumulation, thickening of tubular basement membranes and interstitial fibrosis [5].

Although the mechanisms of renal cell injury in DN are not fully understood, much attention has focused on the role of high glucose per se. Tubular as well as glomerular cells are primary target of hyperglycemia and chronicexposure to elevated blood glucose levels contributes to the functional and phenotypic changes seen in overt DN.

Reactive Oxygen Species in the Development of Diabetic Nephropathy

There is increasing evidence that the overproduction of Reactive Oxygen Species (ROS) is a major factor in the development of diabetic vascular complications as well as diabetes per se [6]. It is now widely recognized that alteration in ROS production in diabetes is a direct consequence of hyperglycemia [6] and that various types of cells including glomerular cells (endothelial, mesangial, and epithelial) as well as tubular epithelial cells are capable of producing ROS in the diabetic milieu.Oxidative stress is thought to be a critical factor in the development of DN. Increased generation of reactive oxygen species occurs in the kidney concomitant with disease progression. Antioxidants prevent glomerular and renal hypertrophy, as well as proteinuria, suggesting a pathogenic role for ROS in the progression of diabetes [7-13].

In the present review, we will focus on CYP metabolites of AA as significant sources of ROS in the kidney in addition to their functional and signaling roles in renal glomerular and tubular cells in various experimental models of nephropathy, including studies by our group.

Metabolism of Arachidonic Acid by Cytochrome P450 Enzymes

Arachidonic Acid (AA), a lipid released as a byproduct of phospholipases, can be metabolized by several pathways: The cyclooxygenase, the lipoxygenase or the Cytochrome P450 (CYP) monooxygenase pathway. In the latter, AA is metabolized by several CYP450 is forms to produce 5,6-, 8,9-, 11,12- and 14,15-Epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acids, and 19- and20-HETEs [14,15] (Figure 1).