Glomerular Repair Retardation via Blocking of Angiotensin II Type 1a Receptor Pathway in a Mouse Glomerulonephritis Model

Abstract

Background/Aims: To examine the role of the angiotensin II (ATII) type 1a receptor (AT1-R) pathway in renal tissue damage and repair, we investigated reversible glomerular injury in a mouse model of habu snake venom (HSV)-induced glomerulonephritis using AT1-R-deficient (AT1a-/-) mice and AT1-R antagonist-treated mice. Methods: Experimental glomerulonephritis was induced by single administration of HSV to AT1a+/+ mice (HSV group) and AT1a-/- mice (KO-HSV group) and AT1-R antagonist-treated BL6 mice (HSV-ARB group). Morphological change and expression levels of type IV collagen, CD31, and vascular endothelial growth factor (VEGF) were analyzed. Results: The HSV group showed increased mesangial matrix expansion on day 7, which returned to preinjection levels by day 56, while mes-angial matrix expansion and increased type IV collagen expression were seen throughout days 7 to 56 in the KO-HSV group. The KO-HSV group showed fewer CD31-positive capillary loops and a marked decrease in the number of VEGF-positive cells in the glomeruli than the HSV group. VEGF administration to the KO-HSV group facilitated glomerular capillary repair and reconstruction. The HSV-ARB group showed the same delay in glomerular repair as that seen in the KO-HSV group. Conclusion: Our results indicate that blocking of the ATII-AT1R pathway delays glomerular repair via angiogenesis inhibition, followed by reduced induction of VEGF.

Modulation of cyclins and p53 in mesangial cell proliferation and apoptosis during Habu nephritis

“…During one phase of mesangiolysis, we found that MC proliferation was activated (day 3). We deduced that the upregulation of growth factors, such as VEGF and PDGF, and inflammatory factors, such as TGF-β, may be the crucial reason for activation of MC proliferation [ 19 ], which promotes the repair process by filling the glomerular cyst with MCs. During the mesangial proliferation phase, cell proliferation, as the dominant biological process, promotes the repair of injuries caused by mesangiolysis.…”

“…In our study, we found that cyclins D1, A and E were activated during different phases, which may be related to various cytokine or protein stimuli. During the early phase of Habu nephritis, platelet and platelet secretory proteins may induce cyclin D1 synthesis [ 23 ], while during the later phase of mesangiolysis and the early phase of mesangial proliferation, activation of growth and inflammatory factors, such as VEGF, PDGF and TGF-β, may stimulate cyclins A and E [ 19 ]. Therefore, the activation of cyclins during different phases mediates the pathological process of Habu nephritis.…”

Angiotensin II Type 1 Receptor Antibodies Are Higher in Lupus Nephritis and Vasculitis than Other Glomerulonephritis Patients

“…Moreover, stimulation of AT1R on lymphocyte T mitigates renal fibrosis (Wen et al 2019 ). AT1R pathway influences glomerular repair in a mouse glomerulonephritis model (Hayashi et al 2012 ). Inhibition of AT1R signalling associated with aberrant podocytes ameliorates albuminuria and has a protective effect on the glomerular filtration barrier (Inoue et al 2019 ).…”