Scientists report new approach to reduce or prevent renal fibrosis

Findings suggest activating type 1 angiotensin receptors on T cells may limit scar formation in the kidney, according to a new study in The American Journal of Pathology


Philadelphia, April 16, 2019

Renal fibrosis, the abnormal accumulation of fibrotic material within the kidney, hinders kidney function and may lead to eventual renal failure. Using genetically altered mice, researchers from Duke University investigated the mechanisms of interaction between the T cells, angiotensin receptors (AT1), and macrophages to understand their role in impeding renal fibrosis. A report in The American Journal of Pathology, published by Elsevier, suggests that selectively activating AT1 receptors on T cells may help treat renal fibrosis.

“These studies are important because they suggest that instead of using global angiotensin receptor blockers, we should develop means of blocking AT1 receptors directly in the kidney while preserving functions of AT1 receptors on immune cells,” explained Steven D. Crowley, MD, of the Division of Nephrology, Departments of Medicine, Duke University, and Durham Veteran Affairs Medical Centers, Durham, NC, USA. “AT1 receptors may attenuate kidney fibrosis by constraining the renal infiltration or differentiation of pro-inflammatory, pro-fibrotic myeloid cells.” Myeloid cells are blood-forming stem cells that differentiate into granulocytes and monocytes.

How T cells and macrophages interact to cause interstitial kidney fibrosis is unclear. Stimulation of AT1 receptors plays a key role in activation of the renin-angiotensin system (RAS), a group of related hormones that helps regulate blood pressure. Angiotensin II, a hormone that is part of the RAS, regulates blood pressure and appears to drive renal fibrogenesis. Inflammation can also contribute to the development of renal fibrosis through the release of pro-fibrotic cytokines that attract macrophages into the kidney.

Genetically altered mice with a T-cell–specific deletion of the dominant mouse AT1 receptor subtype and a control group underwent one-sided ureteral obstruction (UUO) to produce renal obstruction and fibrosis. The investigators found that 14 days after obstruction, mice with this genetic deletion showed increased deposits of collagen, which is indicative of exaggerated fibrosis, and elevated levels of mRNAs for cytokines secreted by Type 1 T helper (Th1) cells compared to control mice. Th1 cells release substances that activate macrophages and are necessary for cell-mediated immune responses.

The investigators also studied mice that were deficient in transcription factor T-bet, which drives and sustains Th1 differentiation in T cells. Without the ability to induce a Th1 response, these mice showed less collagen deposition following UUO compared to control mice. mRNA expression of interferon-γ and interleukin-1β were also down-regulated in mice lacking the Th1 response.

Combined image of pathology slides, scatter plots and tables showing the pro-inflammatory Type 1 T helper cells (Th1) immune responses that may mediate renal fibrogenesis.
Pro-inflammatory Type 1 T helper cells (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 KO) mice. E: Summary data for collagen deposition in WT and T-bet KO mice. F: mRNA expressions of collagen 1 (COL-1), interferon γ (IFN-γ) and interleukin 1β (IL-1β) in kidneys from obstructed WT and T-bet KO mice. *P < 0.05 vs obstructed WT, **P < 0.01 vs obstructed WT. Scale bars: 100μm (A-B); 50 μm (C-D).

Through better understanding of the pathological mechanisms underlying renal fibrosis, researchers hope to develop targeted treatments. “We conclude that activating the AT1 receptor on T cells mitigates renal fibrogenesis by inhibiting Th1 differentiation and renal accumulation of pro-fibrotic macrophages,” said Dr. Crowley. “Our study highlights tissue-specific effects of RAS activation that will warrant consideration as gene therapies that target specific proteins become available.”

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Notes for editors
The article is “Stimulating Type 1 Angiotensin Receptors on T Lymphocytes Attenuates Renal Fibrosis,” by Yi Wen, Nathan P. Rudemiller, Jiandong Zhang, Alexander D. Jeffs, Robert Griffiths, Xiaohan Lu, Jiafa Ren, Jamie Privratsky, and Steven D. Crowley (https://doi.org/10.1016/j.ajpath.2019.02.004). It will appear in The American Journal of Pathology, volume 189, Issue 5 (May 2019) published by Elsevier

This study was supported by the National Institutes of Health; the US Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; the Duke O’Brien Center for Kidney Research; and the American Heart Association.

Full text of the study is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Steven D. Crowley at steven.d.crowley@duke.edu.

About The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org

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The American Journal of Pathology
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