Alamandine alleviates hypertension and renal damage via oxidative-stress attenuation in Dahl rats

Abstract

Alamandine (Ala) is a novel member of the renin–angiotensin-system (RAS) family. The present study aimed to explore the effects of Ala on hypertension and renal damage of Dahl salt-sensitive (SS) rats high-salt diet-induced, and the mechanisms of Ala on renal-damage alleviation. Dahl rats were fed with high-salt diets to induce hypertension and renal damage in vivo, and HK-2 cells were treated with sodium chloride (NaCl) to induce renal injury in vitro. Ala administration alleviated the high-salt diet-induced hypertension, renal dysfunction, and renal fibrosis and apoptosis in Dahl SS rats. The HK-2 cells’ damage, and the increases in the levels of cleaved (c)-caspase3, c-caspase8, and c-poly(ADP-ribose) polymerase (PARP) induced by NaCl were inhibited by Ala. Ala attenuated the NaCl-induced oxidative stress in the kidney and HK-2 cells. DETC, an inhibitor of SOD, reversed the inhibitory effect of Ala on the apoptosis of HK-2 cells induced by NaCl. The NaCl-induced increase in the PKC level was suppressed by Ala in HK-2 cells. Notably, PKC overexpression reversed the moderating effects of Ala on the NaCl-induced apoptosis of HK-2 cells. These results show that Ala alleviates high-salt diet-induced hypertension and renal dysfunction. Ala attenuates the renal damage via inhibiting the PKC/reactive oxygen species (ROS) signaling pathway, thereby suppressing the apoptosis in renal tubular cells.

Factors associated with the progression of mesangial lesions in IgA nephropathy: A comparative analysis of renal re-biopsies

“…Ang-(1–7) is a vasodilator and antiproliferative agent that binds to MasR and is produced by the hydrolysis of Ang II. Alamandine is a part of the alternative RAS and modulates MrgD expression through the PCK/ROS signaling pathway, which is a promising new drug target for kidney and heart protection ( 6 , 7 , 23 , 24 ). In the present study, AT2R expression was significantly lower in the progression than stable group at the baseline and follow-up visits.…”

“…IgAN is characterized by local activation of the RAS and upregulated expression of the angiotensin receptor type 1 (AT1R) (3)(4)(5). New components of the RAS have been identified recently, including angiotensin (Ang)-(1-7), Mas receptor (MasR), Ang-(1-9) and alamandine (6,7). Alamandine is a vasoactive peptide with similar protective actions to Ang-(1-7); it acts through the Mas-related G proteincoupled receptor, member D (MrgD).…”

Counter-regulatory RAS peptides: new therapy targets for inflammation and fibrotic diseases?

“…In a rat model of cardiac ischemia-reperfusion injury, the administration of this peptide reduced the presence of fibrotic markers, increasing the phosphorylation levels of ERK and JNK, while NF-κB decreased ( Song et al, 2019 ). Another mechanism associated with the effects of alamandine was observed in liver and lung, where the peptide attenuated the presence of fibrosis by attenuating autophagy activated by ROS-dependent reactive oxygen species ( Huang et al, 2020 ; Gong et al, 2022 ; Zhao et al, 2022 ). ( Figure 3 ).…”

Counter-regulatory renin-angiotensin system in hypertension: Review and update in the era of COVID-19 pandemic

“…Long-term administration of alamandine to isoproterenol-treated Wistar rats is associated with reduced accumulation of collagens and fibronectin in the heart [171] . A recent study showed that alamandine alleviated high-salt diet-induced hypertension and renal dysfunction via inhibiting the PKC/reactive oxygen species (ROS) signaling pathway, thereby suppressing apoptosis of renal tubular cells [172] . Different types of G proteins, such as G s , G q and G i, can be coupled to MrgDR, which is dependent on ligand selectivity and cell specificity [173] .…”

“…As a new member of the angiotensin family, alamandine has been investigated in a few hypertensive animal models, including SHRs, 2K1C rats, Dahl salt-sensitive rats, and Ang II infusion mice [152] , [162] , [164] , [165] , [172] , [433] . Alamandine was firstly found to lower long-term blood pressure by a single dose in SHRs [152] .…”