Article

Activated intrarenal reactive oxygen species and renin angiotensin system in IgA nephropathy

Department of Physiology, and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112-2699, USA.
Minerva urologica e nefrologica = The Italian journal of urology and nephrology (Impact Factor: 0.7). 04/2009; 61(1):55-66.
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ABSTRACT Immunoglobulin A (IgA) nephropathy is recognized worldwide as the most common primary glomerulopathy. Although the mechanisms underlying the development of IgA nephropathy are gradually being clarified, their details remain unclear, and a radical cure for this condition has not yet been established. It has been clinically demonstrated that the immunoreactivities of intrarenal heme oxygenase-1 (HO-1) and 4-hydroxy-2-nonenal (4-HNE) markers of reactive oxygen species (ROS) and those of intrarenal angiotensinogen (AGT) and angiotensin II (Ang II) markers of renin angiotensin system (RAS) in IgA nephropathy patients were significantly increased as compared to those of control subjects. In an animal study, high IgA of ddY (HIGA) mice were used as an IgA nephropathy model and compared with BALB/c mice, which served as the control. The levels of markers for ROS (urinary 8-isoprostane and intrarenal 4-HNE), RAS (intrarenal AGT and Ang II), and renal damage in the HIGA mice were significantly increased as compared to those in the BALB/c mice. Moreover, an interventional study using HIGA mice demonstrated that the expressions of 2 lines of intrarenal ROS markers (4-HNE and HO-1), 2 lines of intrarenal RAS markers (AGT and Ang II) and renal damage decreased significantly in HIGA mice receiving treatment with the Ang II receptor blocker olmesartan but not in HIGA mice receiving treatment with RAS-independent antihypertensive drugs (hydralazine, reserpine, and hydrochlorothiazide) when compared with HIGA mice that were not treated. These data suggest that intrarenal ROS and RAS activation plays a pivotal role in the development of IgA nephropathy.

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    • "Renin, another key node which is upstream of angiotensin in a number of known pathways, could play a role in IgA nephropathy progression by activation the intra-renal oxygen reactive species [52]. ADAM19 (Meltrin-beta) is the upstream regulator for alpha-2-macrogulbulin (A2M) whose role in renal disease has been identified in several studies [53]. "
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Excessive oxidative stress was evident in NPHS1 kidneys, manifested as an increase expression of p22phox, superoxide production, lipid oxide peroxidation and reduced antioxidant activity. In conclusion, our data indicate that mesangial cell proliferation and the accumulation of extracellular matrix accumulation are associated with the obliteration of glomerular capillaries, causing the reduction of circulation in peritubular capillaries. The injury and rarefaction of peritubular capillaries result in impairment of oxygen and nutrient delivery to the tubuli and interstitial cells, which correlates with the fibrosis, tubular atrophy and oxidative stress observed in NPHS1 kidneys. Valkuaisvirtsaisuutta (proteinuriaa) aiheuttavat munuaissairaudet ovat lasten nefrologian keskeisin ongelma. Vaikea proteinuria saa aikaan nefroottisen oireyhtymän, ja jatkuva valkuaisvirtsaisuus johtaa munuaisen vähittäiseen tuhoutumiseen. 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