Immunosuppression by Mycophenolate Mofetil Mitigates Intrarenal Angiotensinogen Augmentation in Angiotensin II-Dependent Hypertension

被引:7
作者
Satou, Ryousuke [1 ,2 ]
Franco, Martha [3 ,4 ]
Dugas, Courtney M. [1 ,2 ]
Katsurada, Akemi [1 ,2 ]
Navar, L. Gabriel [1 ,2 ]
机构
[1] Tulane Univ, Sch Med, Dept Physiol, New Orleans, LA 70112 USA
[2] Tulane Univ, Sch Med, Hypertens & Renal Ctr Excellence, New Orleans, LA 70112 USA
[3] Inst Nacl Cardiol, Dept Nephrol, Mexico City 14080, DF, Mexico
[4] Inst Nacl Cardiol, Dept Pathol, Mexico City 14080, DF, Mexico
关键词
angiotensinogen; angiotensin II; mycophenolate mofetil; kidney injury; hypertension; IMMUNE CELL INFILTRATION; INFLAMMASOME ACTIVATION; MESSENGER-RNA; KIDNEY INJURY; EXPRESSION; PRESSURE; SYSTEM; GENE; STIMULATION; STRESS;
D O I
10.3390/ijms23147680
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Augmentation of intrarenal angiotensinogen (AGT) leads to further formation of intrarenal angiotensin II (Ang II) and the development of hypertensive kidney injury. Recent studies demonstrated that macrophages and the enhanced production of pro-inflammatory cytokines can be crucial mediators of renal AGT augmentation in hypertension. Accordingly, this study investigated the effects of immunosuppression by mycophenolate mofetil (MMF) on intrarenal AGT augmentation. Ang II (80 ng/min) was infused with or without daily administration of MMF (50 mg/kg) to Sprague-Dawley rats for 2 weeks. Mean arterial pressure (MAP) in Ang II infused rats was slightly higher (169.7 +/- 6.1 mmHg) than the Ang II + MMF group (154.7 +/- 2.0 mmHg), but was not statistically different from the Ang II + MMF group. MMF treatment suppressed Ang II-induced renal macrophages and IL-6 elevation. Augmentation of urinary AGT by Ang II infusion was attenuated by MMF treatment (control: 89.3 +/- 25.2, Ang II: 1194 +/- 305.1, and Ang II + MMF: 389 +/- 192.0 ng/day). The augmentation of urinary AGT by Ang II infusion was observed before the onset of proteinuria. Elevated intrarenal AGT mRNA and protein levels in Ang II infused rats were also normalized by the MMF treatment (AGT mRNA, Ang II: 2.5 +/- 0.2 and Ang II + MMF: 1.5 +/- 0.1, ratio to control). Ang II-induced proteinuria, mesangial expansion and renal tubulointerstitial fibrosis were attenuated by MMF. Furthermore, MMF treatment attenuated the augmentation of intrarenal NLRP3 mRNA, a component of inflammasome. These results indicate that stimulated cytokine production in macrophages contributes to intrarenal AGT augmentation in Ang II-dependent hypertension, which leads to the development of kidney injury.
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页数:13
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