Apr 16, 2019 09:06 PM EDT
The strange growth of fibrotic material within the kidney, renal fibrosis, obstructs kidney function and may lead to eventual renal failure. Duke University's researchers used genetically altered mice to investigate the mechanisms of interaction between the T cells, angiotensin receptors (AT1), and macrophages to understand their role in impeding renal fibrosis. The report of the researchers published in the American Journal of Pathology by Elsevier, recommends that selectively activating AT1 receptors on T cells may help treat renal fibrosis.
In his words, Steven D. Crowley, MD, of the Division of Nephrology, Departments of Medicine, Duke University, and Durham Veteran Affairs Medical Centers, Durham, NC, USA, he said explained that the studies are essential because they suggest that instead of using global angiotensin receptor blockers, they should develop means of blocking AT1 receptors directly in the kidney while preserving functions of AT1 receptors on immune cells.
The researcher stated further that AT1 receptors might attenuate kidney fibrosis by constraining the renal infiltration or differentiation of pro-inflammatory, pro-fibrotic myeloid cells. The blood-forming stem cell, myeloid cells are the ones that differentiate into granulocytes and monocytes.
It is still not clear how T cells and macrophages interact to cause interstitial kidney fibrosis. To activate the renin-angiotensin system (RAS), which is a group of related hormones that help regulate blood pressure, stimulation of AT1 receptors plays a vital role.
Angiotension II, part of the RAS hormone, regulates blood pressure and appears to drive renal fibrogenesis. Another thing that contributes to the development of renal fibrosis is inflammation through the release of pro-fibrotic cytokines that attract macrophages into the kidney.
A control group and genetically altered mice with a T-cell-specific deletion of the dominant mouse AT1 receptor subtype went into one-sided ureteral obstruction (UUO) to produce renal obstruction and fibrosis. The result of the investigation revealed that 14 days after obstacle, 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 macrophage and are necessary for cell-mediated immune responses.
Also in the study, the investigators examined mice that were deficient in transcription factor T-bet, which drives and sustains Th1 differentiation in T cells. With the inability to induce a Th1 response, these mice showed less collagen deposition following UUO compared to control mice. The expression of mRNA of interferon-y and interleukin-1B were also down-regulated in mice lacking the Th1 response.
The researchers hope to develop targeted treatments through a better understanding of the pathological mechanism underlying renal fibrosis. Dr. Crowley said that they concluded that activating the AT1 receptor on T cells mitigates renal fibrogenesis by inhibiting Th1 differentiation and renal accumulation of pro-fibrotic macrophages. Also, Dr. Crowley said that their study highlights the tissue-specific effects of RAS activation that will warrant consideration as gene therapies that target specific proteins become available.
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