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

Abstract

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.

Concentrations of Transition Metal Ions in Rat Lungs after Tobacco Smoke Exposure and Treatment with His-Leu Dipeptide

“…Exposure to tobacco smoke was carried out for six weeks. Treatment with HL (administered by subcutaneous injection, analogously to angiotensin II administration in other studies [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]) started from the third week of exposure to tobacco smoke and lasted four weeks.…”

“…Administering 5 mg HL/kg body weight per day would result in the basal concentration (10 pM) in the whole rat body after about four hours following injection, assuming a 10 min half-life of HL because of the subcutaneous route (in contrast to intravenous injection) and the average rat tissue water content of 65.6% [ 88 ]. Although the chosen dosage may seem relatively low, angiotensin II is administered to rats usually subcutaneously in the concentration range of 0.1–1.5 mg/kg body weight per day, with biological effects observed on the level of the whole organism [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. Therefore, our choice for dosage is higher than that of angiotensin II (calculating it, one should also consider the difference in molecular weights of these peptides, which means that we administered from 14- to 190-fold higher molar content of HL than angiotensin II administered in other studies).…”

“…Therefore, our choice for dosage is higher than that of angiotensin II (calculating it, one should also consider the difference in molecular weights of these peptides, which means that we administered from 14- to 190-fold higher molar content of HL than angiotensin II administered in other studies). However, we should note that we administered HL once per day, opposite to angiotensin II, which was usually administered constantly using an osmotic mini-pump [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ].…”

The Renin-Angiotensin-Aldosterone System in Metabolic Diseases and Other Pathologies

“…However, effects of immunosuppression on intrarenal AGT upregulation and the development of kidney injury in Ang II-dependent hypertension have not been established. Satou et al demonstrated that Ang II-induced upregulation of intrarenal AGT expression, proteinuria, mesangial expansion, and renal tubulointerstitial fibrosis were attenuated by immunosuppression using mycophenolate mofetil (MMF) [ 11 ]. Furthermore, MMF treatment attenuated the augmentation of intrarenal NLRP3 mRNA, a component of inflammasome.…”

Association of shift work and dietary inflammatory potential with all-cause death among us hypertensive population: national health and nutrition examination study, 2005–2010

“…Recent studies have shown that the DII scores were positively associated with systolic blood pressure (SBP) values and prevalence of hypertension, and patients previously diagnosed with cardiovascular disease also tend to have a pro-inflammatory dietary pattern [ 28 – 30 ]. Several novel therapeutic strategies exerting anti-inflammatory and immune-modulating effects improved the long-term prognosis of the hypertensive population via reducing end-organ damage [ 31 , 32 ]. The relationship between DII score and risk of death was reported in a series of studies, in which pro-inflammatory dietary pattern was confirmed to be linked with higher mortality risk [ 33 , 34 ].…”