|Year : 2017 | Volume
| Issue : 1 | Page : 3-9
Association of lipid abnormalities and oxidative stress with diabetic nephropathy
Kamal Kachhawa1, Divya Agrawal2, Bandana Rath3, Sanjay Kumar4
1 Department of Biochemistry, Mahaveer Institute of Medical Sciences and Research, Bhopal, Madhya Pradesh, India
2 Department of Anatomy, Mahaveer Institute of Medical Sciences and Research, Bhopal, Madhya Pradesh, India
3 Department of Pharmacology, MKCG Medical College, Berhampur, Odisha, India
4 Department of Pharmacology, Mahaveer Institute of Medical Sciences and Research, Bhopal, Madhya Pradesh, India
|Date of Web Publication||1-Mar-2017|
Department of Biochemistry, Mahaveer Institute of Medical Sciences and Research, Bhopal - 462 033, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Chronic kidney disease (CKD) is characterized by progressive loss of renal function. Although the burden of CKD in India cannot be assessed accurately, its approximate prevalence is believed to be 800 per million populations (pmp), and the incidence of end-stage renal disease (ESRD) is 150–200 pmp. Diabetic nephropathy is a leading cause of ESRD worldwide. Another cause of ESRD is dyslipidemia, which is one of the most common quantitative lipid abnormalities in patients with CKD. In diabetes, the total cholesterol and triglyceride levels rise as the albumin excretion rate increases, leading to renal injury. Oxidative stress generated by hyperglycemia increases reactive oxygen species production, which causes cellular dysfunction and damage, and ultimately results in diabetic micro- and macro-vascular complications. Therefore, lipids may represent a useful clinical tool for not only identifying patients at a high risk of developing CVD but also assessing the development and progression of renal disease. In this review, we summarize the effects of lipid abnormalities and oxidative stress in patients with diabetes and nephropathy.
Keywords: Diabetes, end-stage renal disease, lipid profile, oxidative stress
|How to cite this article:|
Kachhawa K, Agrawal D, Rath B, Kumar S. Association of lipid abnormalities and oxidative stress with diabetic nephropathy. J Integr Nephrol Androl 2017;4:3-9
|How to cite this URL:|
Kachhawa K, Agrawal D, Rath B, Kumar S. Association of lipid abnormalities and oxidative stress with diabetic nephropathy. J Integr Nephrol Androl [serial online] 2017 [cited 2018 Jun 17];4:3-9. Available from: http://www.journal-ina.com/text.asp?2017/4/1/3/201274
| Introduction|| |
The prevalence of diabetes and its consequent secondary disorders has risen to nearly epidemic proportions in recent years. Diabetes is the leading cause of end-stage renal disease (ESRD) and, consequently, the incidence of ESRD is increasing worldwide. The prevalence of diabetes worldwide was approximately 2.8% in 2000 and is expected to rise to around 4.4% by 2030, according to the World Health Organization. The worldwide prevalence of diabetes is shown in [Figure 1]. The prevalence of chronic kidney disease (CKD) in the India is 17.2%, Singh et al. 2013, and the most common associated risk factor of CKD are hypertension, anemia, and diabetes. Some other Indian study conduct on government employer also show a prevalence rate of 13-15%.
Patients with diabetes and early renal disease (microalbuminuria) have a 3-fold higher risk of mortality, those with overt renal disease (macroalbuminuria) have a 9-fold higher risk, and patients with renal failure, an 18-fold higher risk than patients without renal disease who do not exhibit an elevated risk above that of the general population.
In patients who eventually advance to ESRD, especially in dialysis patients, the prevalence of clinical coronary heart disease is 40%, and CVD-related mortality is 10–30 times higher than that in the general population of the same gender, age, and race.,,
Diabetic nephropathy results in profound dysregulation of several key enzymes and metabolic pathways; this eventually contributes to disordered high-density lipoprotein (HDL), cholesterol, and triglyceride-rich lipoprotein levels. High total cholesterol and non-HDL-cholesterol levels, and low HDL-cholesterol levels are significantly associated with an increased risk of developing renal dysfunction in healthy men.
The oxidative stress generated by hyperglycemia stimulates the production of reactive oxygen species (ROS), which in turn leads to the activation of various redox-sensitive cell signaling molecules and the production of cytotoxic materials. This is followed by cellular dysfunction and damage, ultimately resulting in diabetic micro- and macro-vascular complications. The main objective of this review is to summarize the effects of lipid abnormalities and oxidative stress in patients with diabetes and nephropathy and outline the treatment strategies adopted to circumvent these effects.
| Epidemiology of Abnormal Lipoprotein Metabolism|| |
Hypertriglyceridemia is one of the most common quantitative lipid abnormalities in patients with CKD.,, Hypertriglyceridemia is characterized by increased serum triglyceride levels, along with elevated very low-density lipoprotein (VLDL), small dense low-density lipoprotein (LDL) particles, and low HDL cholesterol levels. All of these particles are characterized by triglyceride-rich apolipoprotein B (apo B)-containing complex lipoproteins, which have significant atherogenic potential.
Several studies have shown that patients with impaired renal function exhibit increased concentrations of triglycerides, even if their serum creatinine levels are within normal limits.,, That dyslipidemia is not just secondary to renal disease has been demonstrated previously in diabetic patients. In both Type 1 and Type 2 diabetes, an unfavorable lipid profile is present at a very early stage of albuminuria, regardless of whether the glomerular filtration rate is normal or elevated., The concentrations of total cholesterol, VLDL, LDL cholesterol, and triglycerides rise with increasing albumin excretion rate in patients with Type 1 diabetes. In addition, there is an increase in LDL mass and atherogenic small dense LDL particles, which correlates with the plasma triglyceride concentrations.,
Diabetic nephropathy causes insulin resistance, which, in turn, promotes hepatic VLDL production.,, Thus, it may be hypothesized that the insulin resistance-driven overproduction of VLDL significantly contributes to the development of hypertriglyceridemia in patients with CKD.
In addition, HDL levels tend to be reduced in diabetic nephropathy, accompanied with a disadvantageous alteration in their composition. In the nondiabetic population, individuals with microalbuminuria exhibit similar lipid abnormalities.
| How Does the Abnormal Lipid Profile Affect Renal Physiology?|| |
It has long been suggested that hyperlipidemia causes renal injury and contributes to the progression of renal disease. Predictive symptoms of renal disease progression have been observed in diabetics even before the appearance of microalbuminuria. In a prospective study of 574 patients with Type 2 diabetes and normal renal function at baseline, Ravid et al. demonstrated that a high cholesterol level was associated with a significantly higher incidence of microalbuminuria as well as cardiovascular events.
There have been a number of observational studies showing that lipid abnormalities are associated with a reduction in kidney function in the general population. It is uncertain if it is the lipid abnormalities that cause the reduction in kidney function, or if impaired renal function or proteinuria itself cause both the lipid abnormalities and reduction in renal function. Samuelsson et al. demonstrated a strong correlation between triglyceride-rich apo B-containing lipoproteins and the rate of progression in nondiabetic patients with CKD. Muntner et al. subsequently showed that individuals with low HDL cholesterol and hypertriglyceridemia at baseline have a higher risk of loss of renal function. The fact that all of the participants in this study (12,728 participants in the atherosclerosis risk in communities) had a baseline creatinine level of 2 mg/dL in men and 1.8 mg/dL in women indicates that hypertriglyceridemia plays a role in the initiation of mild renal insufficiency. That high triglycerides levels are an independent predictor of renal disease was confirmed in a prospective study of 297 patients with Type 1 diabetes.
Notable among the traditional risk factors for CVD in the general population is dyslipidemia. Several observational studies have shown that total, and LDL-cholesterol values are two of the most important independent predictors of cardiovascular morbidity and mortality. In addition, it is well-known that patients with impaired renal function exhibit significant alterations in lipoprotein metabolism, which in their most advanced form, may result in the development of severe dyslipidemia. However, the precise role that these alterations play in the pathogenesis of atherosclerosis in individuals with CKD remains controversial.
| Mechanisms Underlying Abnormal Lipid Metabolism|| |
The role of lipid abnormalities in the pathogenesis of renal injury is still a matter of research. Progressive renal failure especially that associated with proteinuria is accompanied by abnormalities of lipoprotein transport. Several pathogenic mechanisms underlie this pattern of abnormalities. First, urinary protein loss stimulates increased LDL synthesis by the liver. Proteinuria, and the resultant hypoalbuminemia, probably lead to an upregulation of 3-hydroxy-3-methylglutaryl CoA reductase, resulting in hypercholesterolemia. Conversely, low HDL, with the poor maturation of HDL-3 to cholesterol-rich HDL-2, is due to acquire lecithin-cholesterol acyltransferase deficiency secondary to abnormal urinary loss of this enzyme.
Some possible mechanisms of lipid-induced renal injury are as follows:
- Abnormal serum lipid level increases cell proliferation, matrix expansion, and cytokine formation by mesangial cells., Increased cytokine formation could explain the infiltration of macrophages and foam cells observed in the renal tubules and glomeruli of diabetic patients with renal disease 
- Studies in a variety of animal models have shown that hypercholesterolemia accelerates the rate of progression of kidney disease. A high-fat diet causes macrophage infiltration and foam cell formation in rats, leading to glomerulosclerosis ,
- Hyperlipidemia promotes the generation of ROS such as superoxide anion and hydrogen peroxide by monocytes  and mesangial cells, which may oxidize lipoproteins. Oxidized LDL particles further stimulate inflammatory cytokine production, serve as chemoattractants for macrophages and T-lymphocytes, and increase apoptosis of podocytes, endothelial cells, and mesangial cells. They also cause increased production of vasoactive substances, as well as reduced production of vasodilators such as prostacyclin and nitric oxide, which results in enhanced vasoconstriction by vasoconstrictors such as angiotensin II, endothelial-1, and plasminogen activator inhibitor-1 (PAI-1). This effect has significant vascular and renal consequences. Therefore, it is possible that hypertension and dyslipidemia act in concert, each enhancing the other's adverse effect on the kidneys. Oxidative stress, with the resultant increased ROS generation, contributes significantly to these chronic degenerative processes. These observations and a recent study by Orchard et al. suggest that insulin resistance is likely to precede and play a role in the vascular damage associated with diabetic nephropathy.
| How Does Oxidative Stress Provoke Renal Damage?|| |
Patients with diabetes are two to four times more likely to suffer macro- and micro-vascular complications. Moreover, atherosclerosis develops at an early stage and progresses more rapidly in diabetics than in nondiabetic patients, which translates into poor prognosis with high morbidity and mortality in diabetic patients. The microvascular injury mainly targets two major organs, i.e., eye and kidney. Its common manifestations include diabetic retinopathy and nephropathy, which, incidentally, are the leading causes of blindness and ESRD, respectively, in most developed countries.,,
Oxidative stress has been defined as the disruption of the balance between ROS production and the protective antioxidant defense system. The oxidative stress generated by hyperglycemia increases ROS production, which leads to the activation of various redox-sensitive cell signaling molecules and the production of cytotoxic materials. This is followed by cellular dysfunction and damage and ultimately results in diabetic micro- and macro-vascular complications.,,
The cascade of hypoxic-ischemic injury, inflammation, apoptosis, and cell death results in compromised antioxidant functions. ROS increase peroxidation of cellular membrane lipids as well as the oxidation of proteins, which generates protein carbonyl derivatives, producing a high level of MDA in CKD patients, which is a suggestive feature of oxidative stress in long-standing chronic disease.
ROS are a family of molecules that include molecular oxygen and its derivatives, superoxide anion (O2−), hydroxyl racial (HO ·), hydrogen peroxide (H2O2), peroxynitrite (ONOO −), hypochlorous acid (HOCl), nitric oxide (NO), and lipid radicals. Many ROS possess unpaired electrons and are therefore regarded free radicals. Excessive amounts of ROS, after surpassing various endogenous antioxidative defensive mechanisms, oxidize various tissue biomolecules such as DNA, protein, carbohydrates and lipids, and this calamitous state has been commonly referred to as oxidative stress.,,,
| Mechanism of Oxidative Stress-Induced Renal Damage|| |
Four main hypotheses have been proposed to explain hyperglycemia-induced diabetic micro- and macro-vascular complications [Figure 2].
|Figure 2: Hyperglycemia-induced mitochondrial superoxide overproduction activates four pathways underlying hyperglycemic damage|
Click here to view
Polyol pathway flux
Aldose reductase (alditol: NAD[P]+1-oxidoreductase, EC 22.214.171.124) is the first enzyme in the polyol pathway. It is a cytosolic, monomeric oxidoreductase that catalyzes the NADPH-dependent reduction of a wide variety of carbonyl compounds, including glucose. These include sorbitol-induced osmotic stress, decreased (Na + and K +) ATPase activity, an increase in cytosolic NADH/NAD +, and a decrease in cytosolic NADPH. Sorbitol does not diffuse easily across cell membranes, and it was originally suggested that this resulted in osmotic damage to microvascular cells. Aldose reductase reduces the aldehydes generated by the ROS to inactive alcohols, and glucose to sorbitol, using NADPH as a cofactor. In cells where aldose reductase activity is sufficient to deplete reduced glutathione (GSH), oxidative stress is augmented. Sorbitol dehydrogenase oxidizes sorbitol to fructose using NAD + as a cofactor.
Intracellular formation of advanced glycation end products
Advanced glycation ends (AGEs) are found in increased amounts in diabetic retinal vessels  and renal glomeruli. AGEs can arise from the intracellular auto-oxidation of glucose to glyoxal, decomposition of the Amadori product to 3-deoxyglucosone, and fragmentation of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate to methylglyoxal. Production of intracellular AGE precursors damages target cells through three general mechanisms. First, intracellular proteins modified by AGEs have altered function. Second, extracellular matrix components modified by AGE precursors interact abnormally with other matrix components and with the receptors for matrix proteins (integrins) on cells.
Third, plasma proteins modified by AGE precursors bind to AGE receptors on endothelial cells, mesangial cells, and macrophages, inducing receptor-mediated production of ROS.
ROS and nitric oxide react in pathophysiological conditions, to produce dinitrogen trioxide and peroxynitrite. These two toxic reactive nitrogen species cause damage to cellular components (proteins, membranes, nucleic acid) leading to alterations in chromosome, consequently altered cellular functioning and cellular death.
Protein kinase C
Hyperglycemia-induced abnormalities of blood flow and permeability, and activation of protein kinase C (PKC) contributes to increased microvascular matrix protein accumulation by inducing the expression of transforming growth factor-β1, fibronectin, and Type IV collagen both in cultured mesangial cells  and in the glomeruli of diabetic rats. This effect seems to be mediated through the inhibition of nitric oxide production by PKC. Hyperglycemia-induced activation of PKC has also been implicated in the overexpression of the fibrinolytic inhibitor PAI-1, the activation of necrosis factor-kβ in cultured endothelial cells and vascular smooth muscle cells,, and the regulation and activation of various membrane-associated NAD(P) H-dependent oxidases. Hyperglycemia can induce ROS production in vascular and renal cells including tubular epithelial cells and mesangial cells. Increased production of ROS, contributes to endothelial dysfunction, vessel wall thickening, and lesion formation, thereby playing a crucial role in the progressive deterioration of vascular function and structure of renal.
In this pathway, fructose-6-phosphate is diverted from glycolysis to provide substrates for reactions that require UDP-N-acetylglucosamine, such as proteoglycan synthesis and the formation of O-linked glycoproteins. Thus, activation of the hexosamine pathway by hyperglycemia may result in many changes in both gene expression and protein function, which together contribute to the pathogenesis of diabetic complications.
| Association of Lipid Abnormalities Induce Reactive Oxygen Species Formation in Chronic Kidney Disease|| |
Abnormal lipid metabolism induces ROS production by macrophages and mesangial cells. These may oxidize lipoproteins, and these altered lipoproteins have been present in glomeruli and interstitial regions of renal. Mesangial and renal tubular cells can produce ROS, particularly superoxide when exposed to a variety of factors including angiotensin II and PAI-1. Oxidized LDL have been shown to stimulate inflammatory and fibrogenic cytokine production and to cause increased cell apoptosis. These modified lipoproteins also increase production of ROS and lipid peroxidation products may contribute to endothelial injury and may be involved in intensive oxidative modifications of LDL. This is also responsible for the development of atherosclerosis and damage of renal tubules. Lipoprotein may stimulate both glomerular and tubule-interstitial injury through mediators such as cytokines, ROS, and through hemodynamic changes.
| Prevention of Progression of Renal Damage|| |
All patients with elevated lipid levels should be treated with a lipid-lowering diet, which is effective in reducing total cholesterol and LDL-cholesterol levels in those with nephrotic syndrome. However, diet does not completely correct the lipid abnormalities, and very often, hypolipidemic medications are required in conjunction with diet. HMG-CoA reductase inhibitors (statins) are effective in lowering total and LDL cholesterol levels as well as TG levels in those with nephrotic syndrome. Thus, although long-term administration of a multi-antioxidant diet inhibited the development of early diabetic retinopathy in rats, and Vitamin C improved endothelium-dependent vasodilation in diabetic patients,,, low-dose Vitamin E failed to alter the risk of cardiovascular and renal disease in patients with diabetes., The combined effect of lipid-lowering agents and blockers of the renin–angiotensin system on renal outcomes needs further investigation.
The following therapeutic lifestyle changes are suggested for adults with CKD:
- Diet (including fresh fruits on the advice of a dietician)
- Physical activity (regular exercise)
- Abstinence from alcohol and smoking.
| Conclusions and New Progress in This Field|| |
Dyslipidemia is a very common complication of CKD. Disturbances in lipoprotein metabolism are evident even at the early stages of CKD and usually follow a downhill course that parallels the deterioration in renal function. Although many factors other than lipids may contribute to the high cardiovascular event rates observed in patients with CKD, it is likely that dyslipidemia plays a major role.,, Early epidemiologic studies suggesting that high cholesterol levels are likely advantageous for hemodialysis patients were most likely confounded. The severe derangements observed in lipoprotein metabolism in patients with CKD typically results in high triglyceride and low HDL-C levels. Patients of CKD have a substantially increased risk of CVD, and a lipid assessment and treatment module is an important aspect of their care. While there is a clear benefit of statins in stage 1-4 of CKD cases and kidney transplant patients, there does not appear, to be a clear benefit to patients on chronic dialysis, likely because there might be the presence of other risk factors. Nevertheless, we believe that lipids may represent a useful clinical tool in not only identifying patients at a higher risk of CVD but also an assessment of development and progression of renal disease.
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Conflicts of interest
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