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. 2014 Oct;348(4):306-14.
doi: 10.1097/MAJ.0b013e3182a5b6dd.

Renoprotective effects of direct renin inhibition in glomerulonephritis

Kayoko Miyata  1 , Ryousuke Satou, Daisuke Inui, Akemi Katsurada, Dale Seth, Allison Davis, Maki Urushihara, Hiroyuki Kobori, Kenneth D Mitchell, L Gabriel Navar
Affiliations

Renoprotective effects of direct renin inhibition in glomerulonephritis

Kayoko Miyata et al. Am J Med Sci. 2014 Oct.

Abstract

The development of glomerulonephritis causes glomerular injury and renal dysfunction and is thought to increase renin release, thus activating the renin-angiotensin system (RAS). The aims of this study were to demonstrate activation of the intrarenal RAS and determine the effects of direct renin inhibition (DRI) on the progression of glomerulonephritis. Rats were treated with anti-Thy1.1 antibody with or without DRI, aliskiren (30 mg/kg/d). In the glomerulonephritic rats, protein, microalbumin excretion levels, urinary angiotensinogen excretion, glomerular expansion score and intrarenal transforming growth factor-β and plasminogen activator inhibitor-1 mRNA levels were augmented compared with control rats; however, hypertension was not observed in the glomerulonephritic rats, and aliskiren treatment did not modify their blood pressure. The increases in urinary protein (94.7 ± 13.0 mg/d) and microalbumin (7.52 ± 2.6 mg/d) excretion were reduced by aliskiren (43.6 ± 4.5 mg/d of protein and 2.57 ± 0.7 mg/d of microalbumin). Furthermore, the progression of glomerular expansion and elevation of intrarenal transforming growth factor-β and plasminogen activator inhibitor-1 levels were prevented by aliskiren. Importantly, aliskiren suppressed the augmentation of urinary angiotensinogen levels, the increased angiotensinogen expression in the kidneys and the increases in Ang II levels in renal medulla induced by the anti-Thy1.1 antibody. These results suggest that DRI with aliskiren prevents intrarenal RAS activation leading to mitigation of the development of glomerulonephritis. In addition, the renoprotective effects of DRI on glomerulonephritis occur in a blood pressure-independent manner. Accordingly, treatment with aliskiren may be an effective approach to treat glomerulonephritis and other intrarenal RAS-associated kidney diseases.

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Figures

Figure 1
Figure 1
Effects of aliskiren on urinary protein excretion (A) and urinary microalbumin excretion (B) in rats with glomerulonephritis and treated with aliskiren. Data are expressed as mean ± SE. Section (P < 0.05) and double section (p<0.01) indicate significant difference compared to day -4. Asterisk (P < 0.05) and double asterisk (P < 0.01) indicate significant difference compared to the control group. Pound (P < 0.05) and double pound (P < 0.01) indicate significant differences compared to the anti-Thy1.1 glomerulonephritis group.
Figure 2
Figure 2
Effects of aliskiren on glomerular injury in anti-Thy1.1 glomerulonephritis rats. The sections were stained by Periodic acid-Schiff (PAS)-stained sections. Original magnification, ×200 (left). The positive staining (%) in glomeruli is shown in the right panel. Asterisk (P < 0.05) indicates significant difference compared to the control group. Pound (P < 0.05) indicates significant difference compared to the anti-Thy1.1 glomerulonephritis group.
Figure 3
Figure 3
Effects of aliskiren on uAGT elevation in anti-Thy1.1 glomerulonephritis rats. uAGT levels were measured by AGT ELISA. (A) uAGT concentration and (B) uAGT excretion levels. The results were normalized based on urine volume. Section (P < 0.05) and double section (P < 0.01) indicate significant differences compared to day -4. Asterisk (P < 0.01) indicates significant difference compared to the control group. Pound (P < 0.01) indicates significant difference compared to the anti-Thy1.1 glomerulonephritis group.
Figure 4
Figure 4
Effects of aliskiren on AGT expression level in the kidney. (A) AGT protein expression levels detected by Western blot and (B) AGT-immunoreactivity in kidney sections. Original magnification: × 200. Asterisk (P < 0.05) indicates significant difference compared to the control group. Pound (P < 0.05) indicates significant difference compared to the anti-Thy1.1 glomerulonephritis group.
Figure 5
Figure 5
Effects of aliskiren on PRA, plasma Ang II levels, and kidney Ang II levels in anti-Thy1.1 glomerulonephritis rats. PRA (A), plasma Ang II (B), renal cortical Ang II (C) and renal medullary Ang II (D) levels were determined by radioimmunoassay. Kidney Ang II levels were normalized based on kidney weight. Data are expressed as mean ± SE. Asterisk (P < 0.05) and double asterisk (P < 0.01) indicate significant difference compared to the control group. Pound (P < 0.05) and double pound (P < 0.01) indicate significant differences compared to the anti-Thy1.1 glomerulonephritis group.
Figure 6
Figure 6
Effects of aliskiren on TGF-β1 mRNA, PAI-1 mRNA, TGF-β1 protein and PAI-1 protein augmentation in anti-Thy1.1 glomerulonephritis rats. TGF-β1 mRNA (A) and PAI-1 mRNA (B) levels in the kidney cortex were measured by qRT-PCR. TGF-β1 protein (C) and PAI-1 protein (D) levels in the kidney were measured by Western blot. Asterisk (P < 0.01) indicates significant difference compared to the control group. Pound (P < 0.05) and double pound (P < 0.01) indicate significant difference compared to the anti-Thy1.1 glomerulonephritis group.
Figure 7
Figure 7
Effects of aliskiren on PRR mRNA and PRR protein augmentation in anti-Thy1.1 glomerulonephritis rats. PRR mRNA in cortex (A) and PRR mRNA in medulla (B) levels were measured by qRT-PCR. PRR protein levels in kidney cortex (C) were measured by Western blot. Asterisk (P < 0.05) and double asterisk (P < 0.01) indicates significant difference compared to the control group.
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