Curcumin analogue C66 attenuates hypertensive nephropathy by inhibiting JNK-mediated inflammation

Hypertensive nephropathy (HTN) is one of the common, highly disabling, and lethal complication of hypertension and is characterized by increased fibrosis, oxidative stress, and chronic inflammation. Notably, chronic inflammation is throughout the pathogenesis of HTN, even renin-angiotensin-aldosterone system (RAAS) was blocked. Our previous study demonstrated that C66, an anti-inflammatory curcumin derivative compound, prevented various metabolic diseases via inhibiting c-Jun N-terminal kinase (JNK), a key inflammatory target. In the present study, we speculate that C66 could prevent HTN by suppressing JNK-mediated inflammation. Mice were implanted with Ang II mini pump for 4 weeks to developed nephropathy as well as RAAS overactive. A subset of Ang II mini pump-loaded mice were administered C66 (5 and 20 mg/kg/day) for 2 weeks. In Ang II mini pump-loaded mice, the kidneys showed marked renal tubular injuries, fibrosis and inflammation, along with markedly increased pro-inflammatory cytokine production. Interestingly, C66 remarkably reversed these pathological changes via inhibiting JNK-mediated inflammation in vivo. In HTN, immunofluorescent double-staining revealed that JNK activation occurred specifically in renal tubular epithelial cells. Similarly, Ang II induced fibrosis and JNK-mediated inflammation, all of which could be attenuated by C66 treatment in rat renal tubular epithelial cell lines NRK52E cells. In a word, the present study demonstrated that C66 was a potential therapeutic agent for HTN by inhibiting JNK-mediated chronic inflammation.