Enhanced intrarenal oxidative stress and angiotensinogen in IgA nephropathy patients

Abstract

This study was performed to determine whether immunoreactivity of intrarenal hemeoxygenase-1 and angiotensinogen are increased in IgA nephropathy (IgAN) patients. Hemeoxygenase-1 and angiotensinogen immunoreactivity were determined by immunohistochemistry robot system in renal specimens from 39 patients with IgAN. Normal portions of surgically resected kidney served as controls. IgAN patients showed moderate proteinuria (1.1+/-0.2 g/day); however, the control group did not show any proteinuria. Immunoreactivity of intrarenal hemeoxygenase-1 and angiotensinogen in IgAN were significantly increased compared to normal kidneys (2.42+/-0.42 vs 1.00+/-0.26 for hemeoxygenase-1 and 4.05+/-0.40 vs 1.00+/-0.21 for angiotensinogen, arbitrary unit). Even though these IgAN patients did not show massive renal damage, hemeoxygenase-1 and angiotensinogen immunoreactivity were increased in these patients at this time point. These data suggest that activated intrarenal reactive oxygen species-angiotensinogen axis plays some roles in development of IgAN at the early stage and will provide supportive foundation of effectiveness of the renin-angiotensin system blockade in IgAN.

Figure 1

Representative slides for IgA immunostaining from the control group (A) and from the IgA nephropathy group (B).

Figure 2

Enhanced intrarenal oxidative stress in IgA nephropathy patients (A-F). Representative slides for hemeoxigenase-1 immunostaining from the control group (A) and from the IgA nephropathy group (B). Densitometric analysis demonstrated that immunoreactivity of hemeoxygenase-1 in tubules was significantly increased in IgA nephropathy patients compared to the control group (C, 2.42+/−0.42 vs 1.00+/−0.26, arbitrary unit). Representative slides for 4-hidroxy-2-nonenal (4-HNE) immunostaining from the control group (D) and from the IgA nephropathy group (E). 4-HNE-positive cell numbers in tubules was significantly increased in IgA nephropathy patients compared to the control group (F, 589+/−65 vs 368+/−41, per mm²). Activated intrarenal renin-angiotensin system in IgA nephropathy patients (G-L). Representative slides for angiotensinogen immunostaining from the control group (G) and from the IgA nephropathy group (H). Densitometric analysis demonstrated that immunoreactivity of angiotensinogen in tubules was significantly increased in IgA nephropathy patients compared to the control group (I, 4.05+/−0.40 vs 1.00+/−0.21, arbitrary unit). Representative slides for angiotensin II immunostaining from the control group (J) and from the IgA nephropathy group (K). Densitometric analysis demonstrated that immunoreactivity of angiotensin II in tubules was significantly increased in IgA nephropathy patients compared to the control group (L, 11.18+/−3.00 vs 1.00+/−0.46, arbitrary unit).

Figure 3

Correlation with Immunoreactivity of Angiotensinogen. Correlation with immunoreactivity of angiotensinogen was calculated with individual clinical data of both groups. Immunoreactivity of angiotensinogen was significantly correlated positively with urinary occult blood (A, R value = 0.81), urinary protein-to-creatinine ratio (B, R value = 0.72), urinary protein excretion (C, R value = 0.69), and serum creatinine (D, R value = 0.54). Immunoreactivity of angiotensinogen was also significantly correlated negatively with creatinine clearance (E, R value = −0.57).