Interstitial expression of angiotensin II and AT1 receptor are increased in patients with progressive glomerulopathies (original) (raw)
Related papers
Biochemical and Biophysical Research Communications, 2004
The relative roles of angiotensin II (Ang II) type 1 receptor (AT 1 R) and Ang II type 2 receptor (AT 2 R) in immune-mediated nephritis are unknown, and the effect of the blockade of AT 1 R and its indirect counter-activation of AT 2 R relative to the antifibrotic action in this disease is unclear. To address this question, we studied the role of AT 1 R and AT 2 R in anti-glomerular basement membrane nephritis in SJL mice. Groups of mice were treated with either an AT 1 R antagonist (CGP-48933; CGP group), an AT 2 R antagonist (PD-123319; PD group), both (CGP/PD group), or a vehicle (PCt group) from Day 29 to 56. At Day 56 posttreatment, fibrosis-related parameters such as interstitial matrix deposition, and the expression of genes of TGF-b1, plasminogen activator inhibitor-1, and type I collagen were significantly reduced in the kidney in the CGP group. There were no significant effects on these parameters in the PD group. However, this anti-fibrotic action by CGP-48933 was totally abolished by co-treatment with PD-123319 in the CGP/PD group. The gene expression of renin was significantly increased in the kidneys in the CGP and CGP/PD groups, suggesting that CGP-48933 had increased Ang II generation in those groups. In conclusion, counter-activation of AT 2 R by increased Ang II under AT 1 R blockade likely conferred an anti-fibrotic protection in this model.
Kidney International, 2009
Angiotensin II (Ang II) activates at least two receptors, AT1 and AT2, with the majority of its effects-such as vasoconstriction, inflammation, and matrix deposition-mediated by the AT1 receptor. It is thought that the AT2 receptor counteracts these processes; however, recent studies have found proinflammatory and hypertrophic effects of this receptor subtype. To identify the physiological roles of the AT2 receptor in chronic kidney disease, we performed renal ablation in AT2 receptor knockout and wildtype mice. Renal injury caused a greater impairment of renal function, glomerular injury, albuminuria, and mortality in the knockout mice than in the wild-type mice. There was increased fibronectin expression and inflammation in the knockout mice, as shown by augmented monocyte/ macrophage infiltration and higher chemokine monocyte chemotactic protein-1 (MCP-1) and RANTES expression in the remnant kidney. The higher mortality and renal morbidity of the knockout mice was not due to differences in systemic blood pressure, glomerular volume, AT1 receptor, renin, or endothelial nitric oxide synthase expression. Whether activation of the AT2 receptor will have therapeutic benefit in chronic kidney disease will require further study.
AJP: Renal Physiology, 2004
Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model. .-Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT 1R). Recent studies have suggested that type 2 receptor (AT 2R)-mediated signaling inhibits cell proliferation by counteracting the actions of AT1R. The aim of the present study was to determine the effect of AT 2R overexpression on glomerular injury induced by 5 ⁄6 nephrectomy ( 5 ⁄6Nx). AT2R transgenic mice (AT 2-Tg), overexpressing AT2R under the control of ␣-smooth muscle actin (␣-SMA) promoter, and control wild-type mice (Wild) were subjected to 5 ⁄6Nx. In AT2-Tg mice, the glomerular expression of AT 2R was upregulated after 5 ⁄6Nx. Urinary albumin excretion at 12 wk after 5 ⁄6Nx was decreased by 33.7% in AT2-Tg compared with Wild mice. Glomerular size in AT 2-Tg mice was significantly smaller than in Wild mice after 5 ⁄6Nx (93.1 Ϯ 3.0 vs. 103.3 Ϯ 1.8 m; P Ͻ 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor- 1 (TGF-1) in AT2-Tg with 5 ⁄6Nx 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- 1, was decreased in AT 2-Tg mice. These changes in AT2-Tg mice at 12 wk after 5 ⁄6Nx were blocked by the AT2R antagonist PD-123319. Taken together, our findings suggest that AT 2R-mediated signaling may protect from glomerular injuries induced by 5 ⁄6Nx and that overexpression of AT 2R may serve as a potential therapeutic strategy for glomerular disorders.
Angiotensin II and Renal Fibrosis
Hypertension, 2001
Angiotensin (Ang) II, the main peptide of the renin angiotensin system (RAS), is a renal growth factor, inducing hyperplasia/hypertrophy depending on the cell type. This vasoactive peptide activates mesangial and tubular cells and interstitial fibroblasts, increasing the expression and synthesis of extracellular matrix proteins. Some of these effects seem to be mediated by the release of other growth factors, such as TGF-. In experimental models of kidney damage, renal RAS activation, cell proliferation, and upregulation of growth factors and matrix production were described. In some of these models, blockade of Ang II actions by ACE inhibitors and angiotensin type 1 (AT 1 ) antagonists prevents proteinuria, gene expression upregulation, and fibrosis, as well as inflammatory cell infiltration. Interestingly, Ang II could also be involved in the fibrotic process because of its behavior as a proinflammatory cytokine, participating in various steps of the inflammatory response: Ang II (1) activates mononuclear cells and (2) increases proinflammatory mediators (cytokines, chemokines, adhesion molecules, nuclear factor B). Finally, Ang II also regulates matrix degradation. These data show that drugs controlling this complex vasoactive peptide are probably one of the best ways of avoiding fibrosis in progressive renal diseases. (Hypertension. 2001;38[part 2]:635-638.)
Laboratory Investigation, 2012
It is known that angiotensin (Ang)-converting enzyme (ACE) 2 catalyzes Ang II to Ang 1-7 to prevent the detrimental effect of Ang II on blood pressure, renal fibrosis, and inflammation. However, mechanisms of renoprotective role of Ace2 remain largely unclear. The present study tested the hypothesis that deficiency of Ace2 may accelerate intrarenal Ang II-mediated fibrosis and inflammation independent of blood pressure in a model of unilateral ureteral obstructive (UUO) nephropathy induced in Ace2 þ /y and Ace2 À/y mice. Results showed that both Ace2 þ /y and Ace2 À/y mice had normal levels of blood pressure and plasma Ang II/Ang 1-7. In contrast, deletion of ACE2 resulted in a fourfold increase in the ratio of intrarenal Ang II/Ang 1-7 in the UUO nephropathy. These changes were associated with the development of more intensive tubulointerstitial fibrosis (a-SMA, collagen I) and inflammation (TNF-a, IL-1b, MCP-1, F4/80 þ cells, and CD3 þ T cells) in Ace2 À/y mice at day 3 (all Po0.05) after UUO, becoming more profound at day 7 (all Po0.01). Enhanced renal fibrosis and inflammation in the UUO kidney of Ace2 À/y mice were largely attributed to a marked increase in the intrarenal Ang II signaling (AT1-ERK1/2 mitogen-activated protein kinase), TGF-b/Smad2/3, and NF-kB signaling pathways. Further studies revealed that enhanced TGF-b/Smad and NF-kB signaling in the UUO kidney of Ace2 À/y mice was associated with upregulation of an E3 ligase Smurf2 and a loss of renal Smad7. In conclusion, enhanced Ang II-mediated TGF-b/Smad and NF-kB signaling may be the mechanisms by which loss of Ace2 enhances renal fibrosis and inflammation. Smad7 ubiquitin degradation mediated by Smurf2 may be a central mechanism by which Ace2 À/y mice promote TGF-b/Smad2/3mediated renal fibrosis and NF-kB-driven renal inflammation in a mouse model of UUO nephropathy.
AJP: Renal Physiology, 2010
The intrarenal renin-angiotensin system plays a crucial role in the regulation of renal circulation and sodium reabsorption through the activation of vascular, glomerular, and tubular angiotensin II type 1 (AT(1)) receptor signaling. We previously cloned a molecule that specifically interacted with the murine AT(1) receptor to inhibit AT(1) receptor signaling, which we named ATRAP (for AT(1) receptor-associated protein). Since murine ATRAP was shown to be highly expressed in the kidney, in the present study we investigated expression and distribution of human ATRAP in normal kidney and renal biopsy specimens from patients with IgA nephropathy. In the normal human kidney, both ATRAP mRNA and protein were widely and abundantly distributed along the renal tubules from Bowman's capsule to the medullary collecting ducts. In all renal tubular epithelial cells, the ATRAP protein colocalized with the AT(1) receptor. In renal biopsy specimens with IgA nephropathy, a significant positive correlation between ATRAP and AT(1) receptor gene expression was observed. There was also a positive relationship between tubulointerstitial ATRAP expression and the estimated glomerular filtration rate in patients with IgA nephropathy. Furthermore, we examined the function of the tubular AT(1) receptor using an immortalized cell line of mouse distal convoluted tubule cells (mDCT) and found that overexpression of ATRAP by adenoviral gene transfer suppressed the angiotensin II-mediated increases in transforming growth factor-β production in mDCT cells. These findings suggest that ATRAP might play a role in balancing the renal renin-angiotensin system synergistically with the AT(1) receptor by counterregulatory effects in IgA nephropathy and propose an antagonistic effect of tubular ATRAP on AT(1) receptor signaling.
Angiotensin II infusion ameliorates the early phase of a mesangioproliferative glomerulonephritis1
Kidney International, 2002
Angiotensin II infusion ameliorates the early phase of a mesanexperimental and clinical studies have documented a gioproliferative glomerulonephritis. strong nephroprotective effect of antihypertensive ther-Background. Inhibition of the renin-angiotensin system slows apy using angiotensin-converting enzyme (ACE) inhibithe progression of chronic renal disease. tors [1, 2]. Furthermore, there is clear evidence that ACE Methods. To test whether angiotensin II (Ang II) infusion aggravates or ameliorates an acute glomerulonephritis, the inhibitors show beneficial effects that go beyond their peptide was infused (200 ng/min by osmotic minipump) in rats blood pressure lowering effect. However, the mechawith an anti-thymocyte antibody-induced glomerulonephritis nisms of action of ACE inhibitors remain incompletely (ATS). understood. Both experimental and clinical studies re-Results. Ang II significantly increased blood pressure. Following injection of the antibody, similar glomerular binding of vealed that angiotensin II (Ang II) plays a central role rabbit IgG and rat complement C3 was detected in ATS and in the progression of renal disease [3]. The mechanisms Ang IIϩATS rats, indicating no differences in delivery and of Ang II-induced kidney damage are generally attribbinding of the antibody. Ang II infusion, however, induced a uted to direct vasoconstriction, growth promoting and significant reduction in glomerular monocyte infiltration, cell proliferation and matrix expansion in nephritic rats compared profibrotic effects. We and others have characterized the to rats with nephritis without Ang II. The antiproliferative model of anti-Thy-1 induced glomerulonephritis [4-6]. effect of Ang II was inhibited by the Ang II type 1 (AT1) re-The injection of a rabbit anti-rat thymocyte serum inceptor blocker irbesartan, but not by the AT2 receptor blocker duces mesangiolysis, followed by monocyte infiltration PD 123319, indicating that this effect was likely transduced by AT1 receptors. Norepinephrine infusion (600 ng/min) pro-as well as proliferation and matrix expansion. It has been duced a similar degree of hypertension, but did not affect demonstrated that blockade of the renin-angiotensin sysglomerular proliferation in nephritic rats. Ang II induced the tem with ACE inhibitors or Ang II type 1 (AT1) receptor glomerular expression of the cell cycle inhibitor p27 KIP1 and of blockers ameliorates the pathologic changes of the early transforming growth factor- (TGF-) and inhibited expression of monocyte chemotactic protein 1 (MCP-1). phase of the anti-thymocyte antibody-induced glomeru-Conclusion. Ang II surprisingly ameliorates glomerular monolonephritis (ATS) [7, 8]. In addition, we recently found cyte infiltration, proliferation and matrix expansion in ATS that induction of ATS in rats with renovascular hypertennephritis. Ang II-mediated induction of cyclin kinase inhibitors sion aggravated the glomerular damage of ATS in the and TGF- may contribute to the protection of the glomerulus from inflammatory injury by inducing cell cycle arrest and nonclipped kidney [9]. Therefore, we were interested in attenuating activation of local and recruited cells. Alternafurther dissecting the obviously deleterious effects of tively, Ang II might protect the kidney at least in part by less Ang II on the course of ATS. Surprisingly, we discovered inflow of disease activators due to reduction of renal blood that infusion of Ang II led to a marked suppression flow. Therefore, activation of the renin-angiotensin system may have protective effects in certain pathophysiological situations.
Contributions of angiotensin II and tumor necrosis factor-α to the development of renal fibrosis
American Journal of Physiology-Renal Physiology
Angiotensin II upregulates tumor necrosis factor-α (TNF-α) in the rat kidney with unilateral ureteral obstruction (UUO). In a mouse model of UUO, we found that tubulointerstitial fibrosis is blunted when the TNF-α receptor, TNFR1, is functionally knocked out. In this study, we used mutant mice with UUO in which the angiotensin II receptor AT1a or the TNF-α receptors TNFR1 and TNFR2 were knocked out to elucidate interactions between the two systems. The contribution of both systems to renal fibrosis was assessed by treating TNFR1/TNFR2-double knockout (KO) mice with an angiotensin-converting enzyme inhibitor, enalapril. The increased interstitial volume (Vvint) in the C57BI/6 wild-type mouse was decreased in the AT1a KO from 32.8 ± 4.0 to 21.0 ± 3.7% ( P < 0.005) or in the TNFR1/TNFR2 KO to 22.3 ± 2.1% ( P < 0.005). The Vvint of the TNFR1/TNFR2 KO was further decreased to 15.2 ± 3.7% ( P < 0.01) by enalapril compared with no treatment. The induction of TNF-α mRNA and transfo...