Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model

Abstract

Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT(1)R). Recent studies have suggested that type 2 receptor (AT(2)R)-mediated signaling inhibits cell proliferation by counteracting the actions of AT(1)R. The aim of the present study was to determine the effect of AT(2)R overexpression on glomerular injury induced by (5/6) nephrectomy ((5/6)Nx). AT(2)R transgenic mice (AT(2)-Tg), overexpressing AT(2)R under the control of alpha-smooth muscle actin (alpha-SMA) promoter, and control wild-type mice (Wild) were subjected to (5/6)Nx. In AT(2)-Tg mice, the glomerular expression of AT(2)R was upregulated after (5/6)Nx. Urinary albumin excretion at 12 wk after (5/6)Nx was decreased by 33.7% in AT(2)-Tg compared with Wild mice. Glomerular size in AT(2)-Tg mice was significantly smaller than in Wild mice after (5/6)Nx (93.1 +/- 3.0 vs. 103.3 +/- 1.8 microm; P < 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor-beta(1) (TGF-beta(1)) in AT(2)-Tg with (5/6)Nx compared with Wild mice. Urinary excretion of nitric oxide metabolites was increased 2.5-fold in AT(2)-Tg compared with Wild mice. EMSA showed that activation of early growth response gene-1, which induces the transcription of PDGF-BB and TGF-beta(1), was decreased in AT(2)-Tg mice. These changes in AT(2)-Tg mice at 12 wk after (5/6)Nx were blocked by the AT(2)R antagonist PD-123319. Taken together, our findings suggest that AT(2)R-mediated signaling may protect from glomerular injuries induced by (5/6)Nx and that overexpression of AT(2)R may serve as a potential therapeutic strategy for glomerular disorders.

Albumin endocytosis in proximal tubule cells is modulated by angiotensin II through an AT 2 receptor-mediated protein kinase B activation

“…We show that Ang II is operating to stimulate endocytosis via an AT 2 receptor. Our data are consistent with published work (11) showing that overexpression of the AT 2 receptor in mice with glomerular injury reduces urinary albumin excretion and that this effect is completely abolished by the AT 2 antagonist, PD123319. In view of the published work and our experiments, we postulate that AT 2 receptors play an important role in the reabsorption of albumin through an increase of albumin endocytosis in proximal tubule cells.…”

“…Therefore, it is plausible that AT 2 -mediated Ang II stimulation, which induces PKB activation in proximal tubule cells, could decrease the toxic effects of albumin and avoid the loss of albumin through an increase in albumin reabsorption. This hypothesis is made stronger by the observation that, in a glomerular injury-induced mouse model, overexpression of AT 2 decreases the expression of TGF-␤ 1 and urinary albumin excretion (11).…”

“…Interestingly, in patients with proteinuria, treatment with angiotensin-converting enzyme inhibitors and͞or angiotensin (AT 1 ) receptor antagonists is a very effective way of ameliorating urinary loss of albumin (10). Likewise, in a mouse model, overexpression of the AT 2 receptor decreases albuminuria-induced glomerular injury (11). Given these data, angiotensin II (Ang II) is a likely candidate as a regulator of albumin endocytosis.…”

“…The AT 2 receptor is expressed more abundantly during fetal development (8,12). However, studies in adults indicate that the AT 2 receptor could be up-regulated during specific conditions such as sodium depletion or glomerular injury (11,12). The physiological role for AT 2 is not well known.…”

“…The physiological role for AT 2 is not well known. It has been suggested that it plays an important role in the adult animal, probably by counteracting the physiological and pathophysiological effects mediated by the AT 1 receptor (8,11,12).…”