Angiotensin AT2 Receptor is Anti-inflammatory and Reno-Protective in Lipopolysaccharide Mice Model: Role of IL-10

Abstract

Acute kidney injury (AKI) due to endotoxemic insult is predicted by the infiltration of neutrophils, monocytes and macrophages, and the release of pro-and anti-inflammatory cytokines to the site of injury. Earlier, we have demonstrated the role of angiotensin-II type 2 receptor (AT2R) stimulation in reno-protection in lipopolysaccharide (LPS)-induced inflammation and AKI in C57BL6/NHsd mice. Moreover, AT2R activation has been shown to increase the anti-inflammatory cytokine interleukin-10 (IL-10), its role in AT2R-mediated anti-inflammation and reno-protection is unknown. To address this question, in the present study mice were treated with the AT2R agonist C21 (0.3 mg/kg, intraperitoneally), LPS (5 mg/kg, intraperitoneally), or LPS with C21 pre-treatment with or without neutralizing IL-10 antibody. Treatment with C21 alone caused an increase in the plasma and kidney IL-10 levels, which peaks at 2-h, and returned to baseline at 6-h. The C21-induced IL-10 increase was blocked by the AT2R antagonist PD123319 suggesting AT2R’s involvement. LPS treatment caused a profound increase in tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the LPS-induced increase in these cytokines was attenuated by the C21 pre-treatment (1-h prior LPS) both in the plasma and kidney. Neutralizing IL-10 antibody treatment abrogated the C21-lowering of TNF-α and IL-6 in the kidney but not in the plasma. Similar results as related to the cytokines profiles in all the groups were also observed in the heart and spleen. The alteration in early cytokine profile prompted us to measure the markers of renal function (blood urea nitogen and urinary creatinine) in order to analyze the effect of IL-10 neutralization. However, it was too early to observe changes in renal function. Therefore, the renal function and injury markers were again measured at 24 h. Treatment with neutralizing IL-10 antibody attenuated the C21-mediated improvement in indices of the kidney function, but not the biomarkers of renal injury (kidney injury molecule-1 and neutrophil-gelatinase associated lipocalin). Collectively, our data suggest that the involvement of IL-10 in AT2R-mediated anti-inflammation and reno-protection against LPS is complex, mediating the renal cytokine profile and kidney filtration function, but not the plasma cytokine profile and renal injury markers.

The role of renin-angiotensin system in sepsis-associated acute kidney injury: mechanisms and therapeutic implications

“…These effects, mediated primarily via Mas R stimulation, could also be linked to the proposed interaction between Mas R and AT-2R [18], as AT-2R agonists have been shown to reduce tissue NGAL and KIM-1, biomarkers of kidney injury, following LPS challenge [35]. To the best of our knowledge, no study has currently reported the effects of Ang-(1–7) on kidney perfusion.…”

“…These findings were further corroborated in a large animal model of septic shock, where high doses of angiotensin-(1-7) treatment limited the development of septic shock and prevented the increase in creatinine and decrease in creatinine clearance, following induction of sepsis via intraperitoneal injection of autologous feces [34 & ]. These effects, mediated primarily via Mas R stimulation, could also be linked to the proposed interaction between Mas R and AT-2R [18], as AT-2R agonists have been shown to reduce tissue NGAL and KIM-1, biomarkers of kidney injury, following LPS challenge [35]. To the best of our knowledge, no study has currently reported the effects of Ang-(1-7) on kidney perfusion.…”

Progression of retinal choroidal neovascularization by latent human cytomegalovirus infection and immunological signaling among neonatal patients admitted to tertiary care hospital

“…Research has shown that AT1R-induced angiogenesis can produce a significant increase in pro-inflammatory cytokines, 17 whereas AT2R was found to be antagonistically reduced angiogenesis. 18 Recent investigation reported that AT1R-mediated positive regulation of NFκB signal activation ultimately induces the overexpression of different cytokines. 19 NFκB is a transcriptional regulator that resides in the cytoplasm when inactive, bound to inhibitor proteins like IκBα or IκBβ.…”

“…Angiotensin II initiates responses via G protein‐coupled receptors known as AGTR2 (Angiotensin II receptor type‐II), which include AT1R and AT2R. Research has shown that AT1R‐induced angiogenesis can produce a significant increase in pro‐inflammatory cytokines, 17 whereas AT2R was found to be antagonistically reduced angiogenesis 18 . Recent investigation reported that AT1R‐mediated positive regulation of NFκB signal activation ultimately induces the overexpression of different cytokines 19 .…”

The protective effects of a novel AT2 receptor agonist, β-Pro7 Ang III in ischemia-reperfusion kidney injury

“…In comparison, frontline therapy for patients with CKD includes blockade of the renin-angiotensin system (RAS) using angiotensin II receptor blocker (ARB), or the angiotensin-converting enzyme inhibitor (ACEi), which has been widely reported to control proteinuria and reduce the progression of CKD (Cheung et al, 2021;Chu et al, 2021). Recent discoveries on the activation of angiotensin II type 2 receptors (AT2R) suggest potential therapeutic benefits due to anti-inflammatory and anti-fibrotic properties (Castoldi et al, 2016;Rehman et al, 2012), that may protect from kidney damage and the progression of long-term fibrosis due to AKI (Fatima et al, 2021). Since AT2R therapy was introduced, different types of agonists have been trialled in pre-clinical studies, including the agonists CGP42112 (Whitebread et al, 1989), compound 21 (C21) (Wan et al, 2004) and the antagonist, PD123319 (Dudley et al, 1990).…”