Knockout of TRPA1 exacerbates angiotensin II-induced kidney injury

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 Ml 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 W1 mice. Trpa1(-/-) mice had significantly increased expression levels of inflammatory cytokines and their receptors in the kidney. Cultured murine macro-phages 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-1 beta and chemokine (C-C motif) ligand 2 in macro-phages. 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.