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URL: https://pubmed.ncbi.nlm.nih.gov/20042458/

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

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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.

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Figures

👁 Fig. 1.
Fig. 1.
Effects of interventions on structural injury. Glomerulosclerosis, tubular atrophy, and interstitial fibrosis were prominent in control untreated 5/6 nephrectomy (Nx) and AT2RA, and less in angiotensin type 1 (AT1) receptor blocker (ARB) and combined at 12 wk after 5/6 Nx (A; ×100, periodic acid-Schiff). Sclerosis progressed in control untreated 5/6 Nx and AT2RA from biopsy to autopsy with on average doubling of severity (i.e., >100% increase). Average sclerosis increase was significantly decreased in ARB group, with regression in one rat, in contrast to no benefit of AT2RA alone (B). *P < 0.05, ARB vs. AT2RA.
👁 Fig. 2.
Fig. 2.
Collagen content, assessed by HPLC of lysates from renal cortex. Compared with normal kidney, collagen content increased significantly in control untreated 5/6 Nx and AT2RA, with significant decrease in ARB but not combined group. **P < 0.01, normal vs. control untreated 5/6 Nx, normal vs. combined, control untreated 5/6 Nx vs. AT1RA, AT1RA vs. combined. *P < 0.05, normal vs. AT2RA, ARB vs. AT2RA; n = 4 for normal; n = 5–6 for all other groups.
👁 Fig. 3.
Fig. 3.
Representative Western blots of phospho-Erk 2 protein in the renal cortex of rats at 12 wk after 5/6 Nx (A). The expression of phospho-Erk 2 protein is presented as phospho-Erk 2/total Erk 2 ratio (B). **P < 0.01, normal vs. control untreated 5/6 Nx, normal vs. AT2RA. *P < 0.05, AT2RA vs. ARB, AT2RA vs. combined; n = 3 for normal; n = 5–6 for all other groups.
👁 Fig. 4.
Fig. 4.
Expression of plasminogen activator inhibitor-1 (PAI-1) mRNA in situ hybridization in kidney cortex was quantitatively analyzed by SCION Image Software and expressed as % area occupied by PAI-1 mRNA signal. PAI-1 mRNA expression was higher in control untreated 5/6 Nx, and further increased in AT2RA, compared with significant decrease in ARB and combined group. **P < 0.01, control untreated 5/6 Nx vs. AT2RA, ARB vs. AT2RA, AT2RA vs. combined. *P < 0.05, control untreated 5/6 Nx vs. ARB.
👁 Fig. 5.
Fig. 5.
PAI-1 immunostaining at 12 wk after 5/6 Nx (control 5/6 Nx: A, B; ARB: C, D; AT2RA: E, F; combined: G, H). PAI-1 protein paralleled that of PAI-1 mRNA in glomeruli and the tubulointerstitial area. PAI-1 immunostaining was especially increased in sclerotic glomeruli and was markedly increased in control untreated 5/6 Nx and AT2RA-treated rats (A, B, E, F), with less staining in ARB and combined rats (C, D, G, H). A, C, E, G: ×400. B, D, F, H: ×200, anti-PAI-1 staining.
👁 Fig. 6.
Fig. 6.
PAI-1 protein in kidney cortex was evaluated by Western blotting (representative blots), shown as PAI-1/β-actin ratio (B; mean for each group). PAI-1 protein was increased in control untreated 5/6 Nx and AT2RA compared with ARB group, with intermediate levels in combined. **P < 0.01, control untreated 5/6 Nx vs. ARB, ARB vs. AT2RA.
👁 Fig. 7.
Fig. 7.
Wild-type (WT) and PAI-1−/− podocytes collagen secretion in response to ANG II. ANG II induced collagen secretion, measured by ELISA, in WT but not in PAI-1−/− podocytes. This response to ANG II was completely prevented by ARB, with only numerical decrease by AT2RA and combined treatment. *P < 0.05.
👁 Fig. 8.
Fig. 8.
Phosphorylation of Erk was increased by ANG II, with similar inhibition by either ARB or AT2RA or combination. Results are from 2 independent experiments, each in triplicate. *P < 0.05.

References

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