Immunosuppression-Independent Role of Regulatory T Cells against Hypertension-Driven Renal Dysfunctions

Abstract

Hypertension-associated cardiorenal diseases represent one of the heaviest burdens for current health systems. In addition to hemodynamic damage, recent results have revealed that hematopoietic cells contribute to the development of these diseases by generating proinflammatory and profibrotic environments in the heart and kidney. However, the cell subtypes involved remain poorly characterized. Here we report that CD39⁺ regulatory T (T_REG) cells utilize an immunosuppression-independent mechanism to counteract renal and possibly cardiac damage during angiotensin II (AngII)-dependent hypertension. This mechanism relies on the direct apoptosis of tissue-resident neutrophils by the ecto-ATP diphosphohydrolase activity of CD39. In agreement with this, experimental and genetic alterations in T_REG/T_H cell ratios have a direct impact on tissue-resident neutrophil numbers, cardiomyocyte hypertrophy, cardiorenal fibrosis, and, to a lesser extent, arterial pressure elevation during AngII-driven hypertension. These results indicate that T_REG cells constitute a first protective barrier against hypertension-driven tissue fibrosis and, in addition, suggest new therapeutic avenues to prevent hypertension-linked cardiorenal diseases.

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ACKNOWLEDGMENTS

We thank A. Abad, M. Blázquez, and the personnel of the CIC Microscopy, Pathology, and Cytometry units for technical assistance, M. Dosil for comments on the manuscript, and V. Tybulewicz and M. Turner for making available to us the initial stocks of Vav1 and Vav2 knockout mice, respectively.

This work has been supported by grants from the Castilla-León Autonomous Government (CSI101U13), the Spanish Ministry of Economy and Competitiveness (SAF2012-31371, RD12/0036/0002), Worldwide Cancer Research, the Solórzano Foundation, and the Ramón Areces Foundation to X.R.B. P.M. is funded by the Spanish Ministry of Economy and Competitiveness (SAF2011-27330). S.F., M.M.-M., J.R.-V., and A.M.-M. were supported by the Spanish Ministry of Economy and Competitiveness through BES-2010-031386, CSIC JAE-Doc, Juan de la Cierva, and BES-2009-016103 contracts, respectively. Spanish government-sponsored funding to X.R.B. is partially supported by the European Regional Development Fund.

We declare no competing interests.

S.F. participated in all the experimental work, analyzed data, and contributed to the artwork design and manuscript writing. M.M.-M. performed animal-based work, designed experiments, and analyzed data. J.R.-V. analyzed flow cytometry data and carried out histochemical analyses. M.P. and J.M.L.-N. performed experiments related to in vivo renal functions. M.A.S. and M.J.M. collaborated in blood pressure determination experiments. A.M.-M. and P.M. carried out work related to the characterization of kidney-resident hematopoietic cells. C.G.-M. performed and analyzed immunohistochemical experiments on tissue sections. B.A. helped in cell transplantation experiments with Ly5 mice. X.R.B. designed the work, analyzed data, wrote the manuscript, and carried out the final editing of figures.