Abstract
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.
Highlights
Chronic kidney disease (CKD) is a severe complication of hypertension [1,2,3]
We confirmed SIRT3 expression in mouse kidneys and found that SIRT3 decreased in mice subjected to chronic angiotensin II (AngII) infusion compared with the controls infused with saline (Figure 1A and 1B)
Blood pressure markedly increased in those subjected to AngII, but the changes affected by SIRT3 were of no statistical significance (Figure 1C)
Summary
Glomerulosclerosis, renal tubule interstitial fibrosis and proteinuria are the main pathological characteristics of the hypertensioninduced kidney injury [4,5,6]. As the terminally differentiated cells of glomerular filtration barrier, play a key role in maintenance of the glomerular filtration barrier so as to prevent proteinuria in CKD [7, 8]. Podocytes damage or loss can result in renal fibrosis and CKD due to the accumulation of fibrosis factors [9]. Reducing fibrosis factors in kidneys, such as fibronectin and collagen type IV, could alleviate and even reverse renal fibrosis in hypertensive nephropathy. SIRT3 is upregulated by nicorandil and reduced by glibenclamide in dose-dependent manner in podocytes [15]. The function and possible molecular mechanism of SIRT3 in hypertensive nephropathy remains unclear
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