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

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.

Could IL-17A Be a Novel Therapeutic Target in Diabetic Nephropathy?

“…The involvement of redox processes in IL-17A actions has also been described in endothelial and immune cells [66]. Another important signal activated by IL-17A includes the protein kinases, such as RhoA/Rho-kinase, MAPK cascade, and Akt signaling [33,64,66] (Figure 3).…”

“…Thus, IL-17A/NF-κB pathway activation contributes to renal inflammation under diabetic conditions. We have recently described that systemic administration of IL-17A in C57BL/6 mice significantly upregulated kidney Mcp-1 and Rantes gene expression and recruited inflammatory cells to the kidney [64]. Moreover, in experimental angiotensin II induced renal damage, IL-17A neutralization also decreased proinflammatory genes and inflammatory cell infiltration [64,93].…”

“…In fact, several other studies have demonstrated that elevated circulating IL-17A levels, achieved by gene overexpression or intraperitoneal or systemic administration of recombinant IL-17A, are deleterious for the vasculature and the kidney. Increased blood pressure, endothelial dysfunction, and inflammatory cell infiltration in the kidney are involved in this kind of damage [64,65]. Moreover, hypertensive patients have increased circulating IL-17A levels [66,67], suggesting that this cytokine can be involved in the onset of hypertension and hypertension related end-organ damage [68].…”

“…We have recently described that systemic administration of IL-17A in C57BL/6 mice significantly upregulated kidney Mcp-1 and Rantes gene expression and recruited inflammatory cells to the kidney [64]. Moreover, in experimental angiotensin II induced renal damage, IL-17A neutralization also decreased proinflammatory genes and inflammatory cell infiltration [64,93]. These data suggest that the elevated local IL-17A production observed in diabetic kidneys could activate resident renal cells to produce proinflammatory cytokines and chemokines, such as MCP-1.…”

IL-17A as a Potential Therapeutic Target for Patients on Peritoneal Dialysis

“…Interestingly, studies in murine models of hypertension identified γδ T lymphocytes as the main source of IL-17A in hypertrophic hearts [ 59 ], kidneys, and aorta [ 60 ]. Moreover, IL-17A + γδ T lymphocytes were observed in the kidney of patients with hypertensive nephroangiosclerosis [ 61 ]. Currently, there are studies that identified the presence of γδ T lymphocytes in the peritoneal cavity and its relationship with Th17 response.…”