Knockout of TRPA1 exacerbates angiotensin II-induced kidney injury

Abstract

Macrophage-mediated inflammation plays a critical role in hypertensive kidney disease. Here, we investigated the role of transient receptor potential ankyrin 1 (TRPA1), a sensor of inflammation, in angiotensin II (ANG II)-induced renal injury. Subcutaneous infusion of ANG II (600 ng·min−1·kg−1) for 28 days was used to induce hypertension and renal injury in mice. The results showed that ANG II-induced hypertensive mice have decreased renal Trpa1 expression ( P < 0.01), whereas ANG II receptor type 1a-deficient hypotensive mice have increased renal Trpa1 expression ( P < 0.05) compared with their normotensive counterparts. ANG II induced similar elevations of systolic blood pressure in Trpa1−/− and wild-type (WT) mice but led to higher levels of blood urea nitrogen ( P < 0.05), serum creatinine ( P < 0.05), and renal fibrosis ( P < 0.01) in Trpa1−/− mice than WT mice. Similarly, ANG II increased both CD68+/inducible nitric oxide synthase+ M1 and CD68+/arginase 1+ M2 macrophages in the kidneys of both Trpa1−/− and WT mice (all P < 0.01), with higher extents in Trpa1−/− mice (both P < 0.01). Compared with WT mice, Trpa1−/− mice had significantly increased expression levels of inflammatory cytokines and their receptors in the kidney. Cultured murine macrophages were stimulated with phorbol 12-myristate 13-acetate, which downregulated gene expression of TRPA1 ( P < 0.01). A TRPA1 agonist, cinnamaldehyde, significantly inhibited phorbol 12-myristate 13-acetate-stimulated expression of IL-1β and chemokine (C-C motif) ligand 2 in macrophages, which were attenuated by pretreatment with a TRPA1 antagonist, HC030031 . Furthermore, activation of TRPA1 with cinnamaldehyde induced apoptosis of macrophages. These findings suggest that TRPA1 may play a protective role in ANG II-induced renal injury, likely through inhibiting macrophage-mediated inflammation.