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C1q-TNF-related protein-9 (CTRP9) is increasingly recognized as a promising cardioprotective adipocytokine, which regulates biological processes like vascular relaxation, proliferation, apoptosis, and inflammation. We recently showed that CTRP9 enhanced carotid plaque stability by reducing pro-inflammatory cytokines in macrophages. However, the underlying molecular mechanism of CTRP9 on anti-inflammatory response in macrophages still remains unclear. We demonstrated that globular CTRP9 (gCTRP9) significantly reduced oxidized low-density lipoprotein (oxLDL)-induced tumor necrosis factor alpha and monocyte chemoattractant protein 1 expression by suppressing nuclear factor-κB phosphorylation and nuclear translocation in RAW 264.7 macrophages. Treatment with gCTRP9 strikingly increased the level of phosphorylated adenosine monophosphate-activated protein kinase (AMPK). AMPK inhibitor abolished the anti-inflammatory effects of gCTRP9. Moreover, gCTRP9 increased the expression of adiponectin receptor 1 (AdipoR1). Downregulation of AdipoR1 by siRNA could abrogate the activation of AMPK and the anti-inflammatory effects of gCTRP9. These results suggested that gCTRP9 protected RAW 264.7 macrophages from oxLDL via AMPK activation in an AdipoR1 dependent fashion.

Renal fibrosis participates in the progression of hypertension-induced kidney injury. The effect of SIRT3, a member of the NAD+-dependent deacetylase family, in hypertensive nephropathy remains unclear. In this study, we found that SIRT3 was reduced after angiotensin II (AngII) treatment both in vivo and in vitro. Furthermore, SIRT3-knockout mice aggravated hypertension-induced renal dysfunction and renal fibrosis via chronic AngII infusion (2000 ng/kg per minute for 42 days). On the contrary, SIRT3-overexpression mice attenuated AngII-induced kidney injury compared with wild-type mice. Remarkably, a co-localization of SIRT3 and KLF15, a kidney-enriched nuclear transcription factor, led to SIRT3 directly deacetylating KLF15, followed by decreased expression of fibronectin and collagen type IV in cultured MPC-5 podocytes. In addition, honokiol (HKL), a major bioactive compound isolated from Magnolia officinalis (Houpo), suppressed AngII-induced renal fibrosis through activating SIRT3-KLF15 signaling. Taken together, our findings implicate that a novel SIRT3-KLF15 signaling may prevent kidney injury from hypertension and HKL can act as a SIRT3-KLF15 signaling activator to protect against hypertensive nephropathy.

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