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Renoprotective Effects of Direct Renin Inhibition in Glomerulonephritis #MMPMID24165783
Miyata K; Satou R; Inui D; Katsurada A; Seth D; Davis A; Urushihara M; Kobori H; Mitchell KD; Navar LG
Am J Med Sci 2014[Oct]; 348 (4): 306-14 PMID24165783show ga
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/day). In the glomerulonephritic rats, protein, microalbumin excretion levels and urinary angiotensinogen excretion, glomerular expansion score, and intrarenal TGF-? and PAI-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/day) and microalbumin (7.52 ± 2.6 mg/day) excretion were reduced by aliskiren (43.6 ± 4.5 mg/day of protein and 2.57 ± 0.7 mg/day of microalbumin). Furthermore, the progression of glomerular expansion and elevation of intrarenal TGF-? and PAI-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 as well as other intrarenal RAS associated kidney diseases.