Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 May;189(5):981-988.
doi: 10.1016/j.ajpath.2019.02.004. Epub 2019 Apr 15.

Stimulating Type 1 Angiotensin Receptors on T Lymphocytes Attenuates Renal Fibrosis

Yi Wen  1 , Nathan P Rudemiller  1 , Jiandong Zhang  1 , Alexander D Jeffs  1 , Robert Griffiths  1 , Xiaohan Lu  1 , Jiafa Ren  1 , Jamie Privratsky  2 , Steven D Crowley  3
Affiliations

Stimulating Type 1 Angiotensin Receptors on T Lymphocytes Attenuates Renal Fibrosis

Yi Wen et al. Am J Pathol. 2019 May.

Abstract

Most forms of chronic kidney disease culminate in renal fibrosis that heralds organ failure. In contrast to the protective effects of globally blocking type 1 angiotensin (AT1) receptors throughout the body, activating AT1 receptors directly on immune cells may serve protective functions. However, the effects of stimulating the T-cell AT1 receptor on the progression of renal fibrosis remain unknown. In this study, mice with T-cell-specific deletion of the dominant murine AT1 receptor isoform Lck-Cre Agtraflox/flox [total knockout (TKO)] and wild-type (WT) controls were subjected to the unilateral ureteral obstruction model of kidney fibrosis. Compared with WT controls, obstructed kidneys from TKO mice at day 14 had increased collagen 1 deposition. CD4+ T cells, CD11b+Ly6Chi myeloid cells, and mRNA levels of Th1 inflammatory cytokines are elevated in obstructed TKO kidneys, suggesting that augmented Th1 responses in the TKO mice may exaggerate renal fibrosis by driving proinflammatory macrophage differentiation. In turn, T-bet deficient (T-bet knockout) mice lacking Th1 responses have attenuated collagen deposition after unilateral ureteral obstruction. We conclude that activating the AT1 receptor on T cells mitigates renal fibrogenesis by inhibiting Th1 differentiation and renal accumulation of profibrotic macrophages.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Stimulation of type 1 angiotensin receptor on T lymphocytes limits kidney fibrosis and inflammation. A–D: Representative fluorescent images of kidney sections from obstructed Lck-Cre mT/mG mice after 1 (A), 3 (B), 7 (C), and 14 (D) days. E:Agtr1a mRNA expression in purified immune cell lineages and in kidney and heart from Lck-Cre Agtraflox/flox [total knockout (TKO)] and wild-type (WT) mice and normalized to WT in each tissue. F and G: Representative images of collagen 1 (COL-1) staining in kidneys from WT (F) and TKO (G) mice. H: Summary data for percentage of COL-1–positive area in obstructed kidneys from WT and TKO mice. I: mRNA expression of transforming growth factor (TGF)-β, COL-1, and plasminogen activator inhibitor (PAI)-1 in WT and TKO obstructed kidneys. n ≥ 6 for all groups. ∗P < 0.05 versus WT. Scale bars: 50 μm (A–D); 100 μm (F and G). au, arbitrary units; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
Figure 2
Figure 2
Activating the T-cell type 1 angiotensin receptor suppresses accumulation of CD4+ T cells in obstructed kidney. A and B: Representative flow cytometry gating strategy for single cell suspensions from unilateral ureteral obstruction kidney. Live cells were gated for CD45+population, then single cells, then CD11b+ Ly6G- cells, as indicated by boxes and arrows. Among these CD11b+ Ly6G- cells, Ly6Chi populations were isolated, as indicated by boxes. C–E: Cell number of CD4+CD8− or CD4−CD8+ T lymphocytes in obstructed kidneys of Lck-Cre Agtraflox/flox [total knockout (TKO)] and wild-type (WT) mice. F: mRNA expression of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-1β, and IL-17 in WT and TKO obstructed kidneys. ∗P < 0.05 versus obstructed WT. au, arbitrary units; FSC-A, forward scatter area; FSC-H, forward scatter height; SSC-A, side scatter area.
Figure 3
Figure 3
Type 1 angiotensin (AT1) receptors on T lymphocytes inhibit the infiltration of proinflammatory monocytes into the fibrosing kidney. A and B: Representative flow cytometry gating strategy. Live cells were gated for CD45+population, then single cells, then CD3+T cells, as indicated by boxes and arrows. CD3+ T cells were separated into CD4 and CD8 single positive populations, as indicated by boxes.C: Number of CD11b+Ly6Chi inflammatory monocytes in obstructed kidneys from Lck-Cre Agtraflox/flox [total knockout (TKO)] and wild-type (WT) mice. D–F: mRNA expression of tumor necrosis factor (TNF)-α, chemokine (C-C motif) ligand 2 (CCL2), and early growth response (EGR)-2 in wild-type macrophages co-cultured with T lymphocytes with and without AT1 receptor deletion. ∗P < 0.05. FSC-A, forward scatter area; FSC-H, forward scatter height; KO, knockout; SSC-A, side scatter area.
Figure 4
Figure 4
Proinflammatory Th1 immune responses mediate renal fibrogenesis. A–D: Representative Sirius Red/Fast Green–stained sections of obstructed kidneys from obstructed wild-type (WT) and T-bet−/− [T-bet knockout (KO)] mice. E: Summary data for collagen deposition in WT and T-bet KO mice. F: mRNA expression of collagen (COL)-1, interferon (IFN)-γ, and IL-1β in kidneys from obstructed WT and T-bet KO mice. ∗P < 0.05, ∗∗P < 0.01 versus obstructed WT. Scale bars: 100 μm (A and B); 50 μm (C and D). Original magnification: ×100 (A and B); ×200 (C and D). au, arbitrary units.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Jones L.K., O'Sullivan K.M., Semple T., Kuligowski M.P., Fukami K., Ma F.Y., Nikolic-Paterson D.J., Holdsworth S.R., Kitching A.R. IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis. Nephrol Dial Transplant. 2009;24:3024–3032. - PubMed
    1. Kitagawa K., Wada T., Furuichi K., Hashimoto H., Ishiwata Y., Asano M., Takeya M., Kuziel W.A., Matsushima K., Mukaida N., Yokoyama H. Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am J Pathol. 2004;165:237–246. - PMC - PubMed
    1. Meldrum K.K., Misseri R., Metcalfe P., Dinarello C.A., Hile K.L., Meldrum D.R. TNF-alpha neutralization ameliorates obstruction-induced renal fibrosis and dysfunction. Am J Physiol Regul Integr Comp Physiol. 2007;292:R1456–R1464. - PubMed
    1. Mehrotra P., Collett J.A., McKinney S.D., Stevens J., Ivancic C.M., Basile D.P. IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: compensatory role of natural killer cells in athymic rats. Am J Physiol Renal Physiol. 2017;312:F385–F397. - PMC - PubMed
    1. Pindjakova J., Hanley S.A., Duffy M.M., Sutton C.E., Weidhofer G.A., Miller M.N., Nath K.A., Mills K.H., Ceredig R., Griffin M.D. Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction. Kidney Int. 2012;81:379–390. - PMC - PubMed

Publication types

MeSH terms

Substances