Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis

Abstract

Angiotensin type 1 (AT1) receptor blocker (ARB) ameliorates progression of chronic kidney disease. Whether this protection is due solely to blockade of AT1, or whether diversion of angiotensin II from the AT1 to the available AT2 receptor, thus potentially enhancing AT2 receptor effects, is not known. We therefore investigated the role of AT2 receptor in ARB-induced treatment effects in chronic kidney disease. Adult rats underwent 5/6 nephrectomy. Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equivalent glomerulosclerosis: no further treatment, ARB, AT2 receptor antagonist, or combination. By week 12 after nephrectomy, systolic blood pressure was decreased in all treatment groups, but proteinuria was decreased only with ARB. Glomerulosclerosis increased significantly in AT2 receptor antagonist vs. ARB. Kidney cortical collagen content was decreased in ARB, but increased in untreated 5/6 nephrectomy, AT2 receptor antagonist, and combined groups. Glomerular cell proliferation increased in both untreated 5/6 nephrectomy and AT2 receptor antagonist vs. ARB, and phospho-Erk2 was increased by AT2 receptor antagonist. Plasminogen activator inhibitor-1 mRNA and protein were increased at 12 wk by AT2 receptor antagonist in contrast to decrease with ARB. Podocyte injury is a key component of glomerulosclerosis. We therefore assessed effects of AT1 vs. AT2 blockade on podocytes and interaction with plasminogen activator inhibitor-1. Cultured wild-type podocytes, but not plasminogen activator inhibitor-1 knockout, responded to angiotensin II with increased collagen, an effect that was completely blocked by ARB with lesser effect of AT2 receptor antagonist. We conclude that the benefical effects on glomerular injury achieved with ARB are contributed to not only by blockade of the AT1 receptor, but also by increasing angiotensin effects transduced through the AT2 receptor.

Angiotensin-(1-9) Attenuates Cardiac Fibrosis in the Stroke-Prone Spontaneously Hypertensive Rat via the Angiotensin Type 2 Receptor

“…Infusion of PD123 319 in a rat model of glomerulosclerosis induced by 5/6 nephrectomy significantly increased glomerular cell proliferation and kidney fibrosis compared with animals that were nephrectomized alone. 30 Increased collagen I levels have also been shown previously to upregulate MMP-14 expression at the mRNA level, 31 which supports our findings. Moreover, fibrotic tissue remodeling after injury is associated with vascular damage and leakage, which has been shown to be associated with type I collagen remodeling and increased MMP-14 activity in mouse models of age-related dermal fibrosis.…”

mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice

“…Consistent with these observations, both mRNA and protein levels of type IV collagen and fibronectin were significantly increased in PcKOTsc1 glomeruli ( Figure 2, C and D). Moreover, we also observed that mRNA and protein levels of TGF-β1 were significantly enhanced ( Supplemental Figure 2, G and H), whereas the protein expression but not amount of mRNA for angiotensin type 2 receptor (AT2R), which may have renoprotective functions, was reduced in PcKOTsc1 mouse glomeruli (Supplemental Figure 2, G and I) (25)(26)(27). mTORC1 activation in podocytes causes podocyte injury and proteinuria.…”

Calmodulin-dependent Protein Kinase II/cAMP Response Element-binding Protein/Wnt/β-Catenin Signaling Cascade Regulates Angiotensin II-induced Podocyte Injury and Albuminuria

“…Within the glomerulus, Ang II decreases the ultrafiltration coefficient and modulates glomerular capillary permselectivity, leading to proteinuria. It has been reported that Ang II directly influences the functions of podocytes dependent on the Ang II type 1 receptor (44,45). A large body of evidence supports that inhibition of the renin-angiotensin system mitigates many deleterious processes in podocytes, thereby reducing the extent of injury.…”