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Saudi Journal of Kidney Diseases and Transplantation
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LETTER TO EDITOR Table of Contents   
Year : 2003  |  Volume : 14  |  Issue : 4  |  Page : 531-534
Hemodynamic Factors and Oxidative Stress: A Unifying Concept in the Progression of Renal Disease?


Post-graduate Department of Medicine, King Fahad Hospital and Tertiary Care Center, Hofuf, Al-Hasa-31982, Saudi Arabia

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How to cite this article:
Saxena AK. Hemodynamic Factors and Oxidative Stress: A Unifying Concept in the Progression of Renal Disease?. Saudi J Kidney Dis Transpl 2003;14:531-4

How to cite this URL:
Saxena AK. Hemodynamic Factors and Oxidative Stress: A Unifying Concept in the Progression of Renal Disease?. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2021 Jan 19];14:531-4. Available from: https://www.sjkdt.org/text.asp?2003/14/4/531/32991
To the Editor:

The actual mechanism of progression of renal disease is multifaceted that involves both hemodynamic and non-hemodynamic (immu-nologic/oxidative stress) factors. [1] Normal renal function is typically associated with an intact nephronal structure with no tubulointer-stial disease as observed in steroid­sensitive minimal change or mild mesangio­ proliferative nephropathy. Conversely, a reduced renal peritubular perfusion is well recognized in focal segmental glomerulo­sclerosis (FSGS) which is generally associated with nephronal damage in the form of tubulointerstitial fibrosis. [2] Thus, there appears to be a spatial association between the renal perfusion and nephronal structural integrity. Animal studies have confirmed that the decline in peritubular capillary flow heralds the development of tubulointerstitial fibrosis. [3]

The reduction of renal perfusion is likely to be an expression of glomerular capillary endothelial dysfunction. The endothelial cells in nephrosis express pro-coagulant instead of anticoagulant surface and vasoconstrictive rather than vasodilatory activity, thus reducing the renal perfusion. [4],[5] The higher incidence of endothelial cytotoxicity impairing the glomerular basement membrane anionic charges among the individuals with FSGS having 'circulating factor' (vascular permea­bility factor) in their serum, in contrast to those with minimal change/ mild mesangioproli­ferative nephropathies, is an indicator of strong relationship between endothelial dysfunction and intrarenal hemodynamic disturbances. [4],[5]

Reactive oxygen species (ROS) are impli­cated in cell signalling, gene transcription, mitosis, apoptosis and vasoconstriction. [6] The cellular sources of ROS are multiple, such as NADPH oxidase, lipooxygenase, cyclooxygenase from plasma membrane; electron transport system from mitochondria; xanthine oxidase, hemoglobin, transition metals (Fe + + / + + + Cu + / + +) from cytosol and cytochrome P-450 from endo­plasmic reticulum. [7] Increase in intracellular meta-bolism results in enhanced production of ROS. In excess, ROS and their products are capable of causing glomerular endo­thelial cytotoxicity through oxidative damage which results in increased levels of oxidized LDL and advanced glycation end products (AGEs) of carbohydrates, fats and proteins. 8 Increase oxidative stress to the glomerular endothelial cells induces endothelial cellular dysfunction and, in excessive amount, results in enhanced apoptosis. In response to such oxidative injury, endo­thelial cells may increase the production of vasoactive substances, such as angiotensin-II, endothelin and thromboxane A 2 (TBX-A 2 ) while the production of endothelin dependent vasodilator, nitric oxide (NO), becomes defective as well as neutralized by excessive amount of ROS. [9]

Such a pro-vasoconstrictive state is likely to produce hemodynamic maladjustment through prominent efferent arteriolar vasoconstriction and consequently raised intraglomerular pressure in conjunction with significantly reduced flow to peritubular capillaries that supply the tubulointerstitial compartment. The presence of intra-glomerular hypertension (IGH) in combination with the reduced renal blood flow and additive effects of oxidative stress to endothelial cell can induce vascular inflammatory gene expression such as vascular cellular adhesion molecule (VCAM), mono­nuclear cell infiltration and pro-coagulant surface expression which could culminate in injury to glomerular cell inducing glomerulo­sclerosis. [9] The administration of vasodilators and antioxidants has been reported to reduce glomerular endothelial cytotoxity. The role of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor (AT 2 ) blockers has been practically established in reducing the rate of progression of renal disease among patients with both diabetic and non-diabetic renal disease. [10] These agents reduce IGH through their vasodilatory action predominantly on the efferent arterioles of the glomeruli. [11] In experimental animal models of chronic renal injury, such renoprotection can virtually eliminate progression of the renal injury, provided that therapy is started at the time of injury. In humans with chronic renal injury, renoprotection has been successfully demonstrated only late in the course of the renal disease. The rate of progression to end-stage renal failure can be delayed, but progression continues at a slower pace. Further study is required to determine whether earlier intervention can better preserve nephronal structure and function. [12]

Antioxidants like vitamin C, vitamin E (tocopherol), and beta-carotene have been shown to regenerate glutathione. Impaired endothelial dependent vasodilatation was found to be markedly improved by vitamin C in essential hypertension. [13] The damage done to the biomolecules by ROS is kept in check by a complex network of antioxidant defense and repair systems, synthesized within the human body. Vitamin E prevents damage to lipids by oxygen free radicals. [14] When highly reactive species attack lipids within mem­branes or lipoproteins, they set off the chain reaction of lipid peroxidation. [15] Vitamin E halts this chain reaction and acts as a chain­breaking inhibitor of lipid peroxidation. Elevated lipid peroxidation has been observed in many diseases including diabetes mellitus and atherosclerosis. [16] Many studies have shown improved vascular endothelial function in diabetic patients with vitamin E at doses ranging from 600-1000 units/day for two to three months. [17],[18]

This information puts forward a supportive view point that the body's oxidant/antioxidant imbalance is conceivably responsible for the provocation of glomerular endothelial dysfunction and consequential hemodynamic maladjustment. Therefore, prudently planned use of vasodilators preferably ACEI and AT 2 receptor blockers in conjunction with the optimal antioxidant therapy, seem to have potentials to improve the renal function and prevent the progression of renal disease. A strategy for future trials is already in evolution placing emphasis on more sensitive outcome measures so as to achieve greater statistical power to decode these principles into practice.

 
   References Top

1.Baldwin DS. Chronic glomerulonephritis: non­immunologic mechanism of progressive glome-rular Kidney Int 1982; 21: 109-20.  Back to cited text no. 1    
2.Futrakul P, Sitprija V, Yenrudi S. Glomerular endothelial dysfunction determines disease progression: a hypothesis. Am J Nephrol1997; 17: 533-540.  Back to cited text no. 2    
3.Bohle A, Mackensen-Haen S, Wehrmann M. Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press Res1996; 19: 191-5.  Back to cited text no. 3  [PUBMED]  
4.Koyama A, Fujisaki M, Kobayashi M, Igarashi M, Narita M. A glomerular permeability factor produced by human T cell hybridomas. Kidney Int 1991: 40: 453-60.  Back to cited text no. 4    
5.Savin VJ, Sharma R, Sharma M et al. Circulating factor associated with increased vascular permeability to albumin in focal segmental glomerulosclerosis. N Engl J Med 1996; 334: 878-83.  Back to cited text no. 5    
6.McIntyre M, Bohr DF, Dominiczak AF. Endothelial function in hypertension : the role of superoxide anion. Hypertension 1999;34:539-45.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Kunsch C, Medford RM. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res1999; 85:753-66.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Kitiyakara C, Gonin J, Massy Z, Wilcox CS. Non-traditional cardiovascular disease risk factors in end stage renal disease: Oxidate stress and hyperhomo-cystinemia. Curr Opin Nephrol Hypertens 2000; 9: 477-87.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Ou ZL, Natai Y, Natori Y. Transient and sequential expression of chemokine in RNA in glomeruli in puromycin amino­nucleoside nephrosis. Nephron. 2000;85: 254-7.  Back to cited text no. 9    
10.Garg J, Bakris GL Angiotensin converting enzyme inhibitors or angiotensin receptor blockers in nephropathy from type 2 diabetes. Curr Hypertens Rep 2002;4:185-90.  Back to cited text no. 10    
11.Walser M. Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N Engl J Med 2002;346:705-7.  Back to cited text no. 11  [PUBMED]  
12.Myers BD, Boothroyd D, Olshen RA. Angiotensin-converting enzyme inhibitor for slowing progression of diabetic and nondiabetic kidney disease: J Am Soc Nephrol 1998;9:S66-70.  Back to cited text no. 12    
13.Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Vitamin C improves endothelium dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 1998;97:2222-9.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Parks E, Traber MG. Mechanism of Vitamin E regulation: research over past decade and focus on the future. Antioxid Redox Signal 2000;2:405-12.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Nourooz-Zadeh J, Rahimi A, Tajaddini­Sarmadi J et al. Relationships between plasma measures of oxidative stress and metabolic control in NIDDM. Diabetologia 1997;40:647-53.  Back to cited text no. 15    
16.Oranje WA, Wolffenbuttel BH. Lipid peroxidation and atherosclerosis in type II diabetes J Lab Clin Med 1999; 134:19-32.  Back to cited text no. 16    
17.Laight DW, Carrier MJ, Anggard EE. Antioxidants, diabetes and endothelial dysfunction Cardiovasc Res 2000;47:457-64.  Back to cited text no. 17    
18.Skyrme-Jones RA, O'Brian RC, Berry KL, Meredith IT. Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized placebo­controlled study. J Am Coll Cardiol 2000; 36:94-102.  Back to cited text no. 18    

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Correspondence Address:
Anil K Saxena
Post-graduate Department of Medicine, King Fahad Hospital and Tertiary Care Center, Hofuf, Al-Hasa-31982
Saudi Arabia
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PMID: 17657129

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