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This effect results from the inhibition of NADPH oxidase and consequently a reduced production of the superoxide anion. The parameters evaluated were blood pressure and markers of oxidative stress and endothelial function BH4. There were significantly lower levels of and a greater availability of serum BH4 in the apocynin-treated animals versus the control group and the two other drug treatments.
The present findings suggest that apocynin in conjunction with a coadjuvant for modulating blood pressure may be useful for controlling the progression of CRF.
In adults, CKD is defined as the presence of a renal structural alteration, demonstrable by specialized urine tests showing urinary sediment as well as imaging or histopathological studies. This condition persists for a minimum of 3 months and its onset is not always accompanied by impaired renal function [ 2 ]. Although alterations in kidney tissue structure, redox balance and endothelial function are reversible in stages 1, 2 and 3, these conditions are irreversible once reaching stages 4 and 5 [ 2 ], having deteriorated the antioxidant defenses beyond repair.
The complications in these cases are mainly caused by the elevated production of reactive oxygen species ROS and reactive nitrogen species RNS , thus altering the oxidant—antioxidant balance. ROS and RNS are an integral part of metabolism, stress and inflammation [ 6 ] and have been extensively studied in disorders of the renal system. Since numerous reports confirm the importance of the oxidative state in renal tissue, antioxidant therapy has become a part of the preventive and regulatory treatment for CKD, delaying its progression KDOQI 3 and consequently the appearance of the terminal phase TCKD [ 7 , 8 ].
Factors that promote oxidative imbalance are a fundamental part of the basic pathophysiological mechanisms of renal disorders. Ischemic or toxic phenomena, which can engender acute damage to the tubule, may be accompanied by excessive production of ROS. In chronic kidney damage of metabolic origin e. The natural defense system against oxidative stress consists mainly of nonenzymatic antioxidants e. All these elements are closely related to the progression of the different stages of CKD [ 4 ].
In patients with damaged renal function, excessive levels of ROS and other uremic toxins of an oxidizing nature disrupt the redox balance and overcome the capacity of the antioxidant defense [ 10 ]. The different isoforms of Nox are Nox1, Nox2 and Nox4 [ 11 ], the latter showing greater expression in endothelial cells than Nox2 [ 10 ]. Under conditions of oxidative stress, however, Nox2 [ 12 ] generates eight times more of the superoxide anion , increasing its level 2 to 3 times.
Hence, reaches a greater concentration than other isoforms in endothelial cells [ 13 ]. At the level of arterioles interlobular, arcuate, afferent, efferent and rectal vessels , the resulting endothelial dysfunction is characterized by altered regulation of vasodilation and vascular tone, leading to ischemia and finally to renal parenchymal necrosis. Ang II is implicated in the development of various cardiovascular and renal pathologies. Apart from being synthesized by the renin—angiotensin—aldosterone system RAAS , it is produced by alternate enzymatic pathways mediated by cathepsin G, chymase, chymostatin-sensitive angiotensin-generating enzyme CAGE and tissue plasminogen activator T-PA.
Hence, each of these pathways can indirectly contribute to increased vascular tone [ 16 ]. On the other hand, 4-hydroxymethoxyacetophenone apocynin , isolated from the medicinal plant Picrorhiza kurroa , has gained recognition as an inhibitor of Nox.
Although the mechanism of action is not yet completely clear, it is known that apocynin inhibits assembly of the cytoplasmic subunits of Nox: p47phox, p67phox and p21rac with gp91phox and p22phox of membranes [ 17 , 18 ]. Apocynin binds to p47phox in the same region in which the latter protein binds to p22phox. Due to its effects on redox balance and vascular tone, the Nox enzyme has become an important therapeutic target.
The probable decrease in production was explored as well as its effect on the pathophysiology of CKD. This investigation is part of the current effort to test new inhibitors of Nox for their possible renoprotective effect. The long-term aim is to improve the quality of life of patients while reducing the morbidity and mortality of CDK.
Two of the drugs, captopril and losartan, are currently employed in clinical practice, while the test drug was apocynin. A left paravertebral cut was made in the dorsal region of the mouse with a scalpel, dissecting the skin, muscle and adipose tissue to allow for the localization of the left kidney at the retroperitoneal level. The parietal and visceral peritoneum was dissected and the left kidney was momentarily exposed.
At the right paravertebral level, the retroperitoneum was dissected to reach the hilum of the right kidney, where the renal vessels and renal pelvis renal hilum were ligated with silk thread 4—0 to remove the kidney total right nephrectomy. The retroperitoneum and muscle were then sutured with 4—0 silk thread and the skin with 4—0 nylon. The animals were returned to their individual cages.
Subsequently, the third of viable renal tissue was placed on a cubic support made of aluminum foil , oriented in a transverse direction and completely covered with a freezing gel O.
Louis, MO. Upon completion of this time, tissues were washed three times 10 min each with PBS and then covered with Vectashield H a fluorescence protector and a resin in order to view the specimens using confocal microscopy Olympus America INC. FV [ 24 ]. Samples were placed in 2 mL aliquots, centrifuged for separation of the serum and globular package.
The serum was separated with Sali pipettes in aliquots to make the determination of BH 4. Mice were anesthetized by i. The left carotid artery was channeled with a polyethylene cannula I. The other end of the cannula was connected to a complete BLPR WPI transducer linked to DUO software for the acquisition of data, which were recorded for 15 min under stable conditions.
Mice were considered hypertensive when the SBP was greater than or equal to 30—40 mmHg compared to the control group sham [ 26 ]. There was an In situ evaluation of superoxide anion in mouse renal cortex tissue at 14 days postnephrectomy. The greatest reduction in the level of was found with apocynin. However, the only significant difference was in the latter case Only the apocynin-treated group showed an increased bioavailability of BH 4.
Measurement of the systolic blood pressure SBP [mmHg] at 14 days postnephrectomy. The efficacy of apocynin in modulating the progression of CKD was compared to that of two drugs in clinical use; captopril and losartan.
The parameters measured were in renal tissue a marker of oxidative stress and BH 4 in serum an indicator of endothelial function , as well as blood pressure.
These three parameters are considered to be altered in the progression of the CKD. In addition, the effectiveness of apocynin was compared to that of captopril and losartan as representative drugs for their groups.
This trend was not observed in the sham group. The data suggest that Ang II influences the production of by the direct activation of Nox through its AT1 receptor, as well as by the inherent participation of this enzyme.
Hence, levels were diminished by the treatment with losartan and apocynin, the latter showing the best results. This apparently owes itself to their inhibitory activity of apocynin on the assembly of Nox subunits [ 10 ]. On the other hand, captopril did not display efficacy in lowering the levels of , since the production of Ang II is not completely limited by inhibiting ACE. Consequently, there is a latent capacity for the generation of by stimulation of Nox [ 27 ]. The interaction of with BH 4 apparently caused the oxidation of the latter, which would diminish its bioavailability for the coupling and enzymatic activity of endothelial nitric oxide synthase eNOS.
Compared to captopril and losartan, apocynin demonstrated a superior effectiveness in this respect. Inhibition of the subunits of Nox engendered a reduced level of and less oxidation of BH 4. Consequently, the progression of renal damage is delayed and the complications and mortality of CKD are diminished. The cause of high blood pressure was a greater peripheral vascular resistance, conditioned by a decrease in the area of glomerular filtration, mesangial proliferation, tubulointerstitial inflammation and glomerulosclerosis renal remodeling , in addition to the production of ROS stimulated by Ang II at the AT1 receptor upon the activation of Nox.
On the other hand, Ang II also activates its AT1 receptor at the vascular level, exhibiting independent activity in the production of ROS and consequently the modulation of vascular tone.
As previously mentioned, high blood pressure seems to result from other mechanisms as well, such as renal remodeling and Ang II activity itself, both of which participate in increased vascular resistance [ 30 , 31 ]. Consequently, there is a reversal of the remodeling generated by profibrotic and inflammatory processes at the vascular and renal levels, which in turn has the beneficial hemodynamic effect of regulating blood pressure in the inferior renal capsule IRC [ 31 ].
However, the lack of effect of apocynin on blood pressure could possibly be overcome by administering it with a coadjuvant for the treatment of CKD. The current findings indicate that apocynin has advantages over losartan and captopril; drugs now used clinically to treat CKD. It seems to better counteract the production of the and endothelial dysfunction.
Unlike losartan and captopril, on the other hand, apocynin did not show the ability to reduce the high blood pressure characteristic of CKD. Hence, the combination of apocynin with an antihypertensive drug acting as an adjuvant could possibly be employed to treat CKD and reach the therapeutic aim through synergism.
We thank Bruce Allan Larsen for proofreading this manuscript. The authors have no conflict of interests in relation to the products or techniques reported in this manuscript. The authors alone are responsible for its content and writing. Read article at publisher's site DOI : To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.
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