Interleukin 17A Participates in Renal Inflammation Associated to Experimental and Human Hypertension.

Macarena Orejudo,Alberto Ortiz,Adrian M Ramos,Javier Rández-Garbayo,Pablo Cannata-Ortiz,Laura Santos-Sánchez,Marta Ruiz-Ortega,Sergio Mezzano,Ana Garcia-Redondo,Raquel Rodrigues-Diez,Raul R Rodrigues-Diez,Rafael Selgas,Carolina Lavoz

doi:10.3389/fphar.2019.01015

Abstract

Hypertension is now considered as an inflammatory disease, and the kidney is a key end-organ target. Experimental and clinical studies suggest that interleukin 17A (IL-17A) is a promising therapeutic target in immune and chronic inflammatory diseases, including hypertension and kidney disease. Elevated circulating IL-17A levels have been observed in hypertensive patients. Our aim was to investigate whether chronically elevated circulating IL-17A levels could contribute to kidney damage, using a murine model of systemic IL-17A administration. Blood pressure increased after 14 days of IL-17A infusion in mice when compared with that in control mice, and this was associated to kidney infiltration by inflammatory cells, including CD3+ and CD4+ lymphocytes and neutrophils. Moreover, proinflammatory factors and inflammatory-related intracellular mechanisms were upregulated in kidneys from IL-17A-infused mice. In line with these findings, in the model of angiotensin II infusion in mice, IL-17A blockade, using an anti-IL17A neutralizing antibody, reduced kidney inflammatory cell infiltrates and chemokine overexpression. In kidney biopsies from patients with hypertensive nephrosclerosis, IL-17A positive cells, mainly Th17 and γδ T lymphocytes, were found. Overall, the results support a pathogenic role of IL-17A in hypertensive kidney disease-associated inflammation. Therapeutic approaches targeting this cytokine should be explored to prevent hypertension-induced kidney injury.

Highlights

Hypertension is a prevalent disorder and the second leading cause of kidney failure after diabetes (Coffman, 2011)
We have developed a novel model of continuous infusion of systemic Interleukin 17A (IL-17A) in mice, resembling chronically elevated IL-17A levels found in prehypertensive patients (Yao et al, 2015)
There was a nonsignificant trend toward higher kidney Kim-1 messenger RNA (mRNA) levels, while Ngal was upregulated by IL-17A infusion (Figure 2)

Summary

Introduction

Hypertension is a prevalent disorder and the second leading cause of kidney failure after diabetes (Coffman, 2011). It may be complicated by target organ damage, including cardiovascular, brain, and kidney injuries. Interleukin 17A (IL-17A), the effector cytokine of Th17 cells, has emerged as a promising therapeutic target in immune and chronic inflammatory diseases, including hypertension and chronic kidney disease (Caillon and Schiffrin, 2016; Solak et al, 2016; Cortvrindt et al, 2017). IL-17A is considered as a pleiotropic cytokine involved in tissue inflammation and destruction through the increased expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and matrix metalloproteases (Von Vietinghoff and Ley, 2010; Cortvrindt et al, 2017)

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