SIRT3-KLF15 signaling ameliorates kidney injury induced by hypertension

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.

MiR‐101a ameliorates AngII‐mediated hypertensive nephropathy by blockade of TGFβ/Smad3 and NF‐κB signalling in a mouse model of hypertension

“…Therefore, we wondered whether miR‐101a ameliorated hypertensive kidney injury induced by AngII injection via targeting TGFβRI or not. Podocytes, highly specialized epithelial cells of glomerular filtration barrier, are important for maintaining glomerular filtration barrier and can generate various fibrosis factors under damage . Our data showed that restoring mir101a expression in mouse podocyte cells down‐regulated TGFβRI expression.…”

“…Renal fibrosis is one of the key pathways involved in hypertensive kidney injury . Histology images showed that renal fibrosis was attenuated in AngII+miR‐101a group compared to AngII and AngII+scramble groups (Figure A).…”

SIRT3 activator honokiol ameliorates surgery/anesthesia‐induced cognitive decline in mice through anti‐oxidative stress and anti‐inflammatory in hippocampus

“…Microglia‐induced oxidative stress and neuron stem cell dysfunction can be attenuated by SIRT3 overexpression through mitochondrial apoptosis pathway, including the decreased mitochondrial permeability transition pore (mPTP) opening, reduced mitochondrial cytochrome C release to cytoplasm, declined Bax/Bcl‐2 ratio and inhibition of caspase‐3/9 activity . Moreover, HNK, as an activator of SIRT3, can also ameliorate kidney injury induced by hypertension via activating SIRT3/KLF15 signaling pathway . Besides, utilizing the Sirt3‐knockout mice and the overexpression of SIRT3 by lentivirus transfection, other studies showed that SIRT3 can protect against cardiac fibrosis by inhibiting myofibroblasts trans‐differentiation via regulation of the STAT3‐NFATc2 signaling pathway .…”

Sirtuins and Accelerated Aging in Scleroderma

“…In some cases, the observed mechanistic effects of SIRTs are so diverse, that it is difficult to narrowly classify them [69, 88, 91, 120]. Specific intracellular signaling molecules or pathways interacting functionally with or targeted directly by SIRTs include adenosine monophosphate-activated protein kinase (AMPK) – angiotensin-converting enzyme 2 (ACE2) signaling [69, 104], peroxisome proliferator-activated receptor (PPAR)γ [97], signal transducer and activator of transcription (STAT)3 [108], mammalian target of rapamycin (mTOR) [99, 102], nuclear factor erythroid 2-related factor 2 (Nrf2) [91, 117], Krüppel-like factor (KLF)15 [110], forkhead fox O1 (FOXO1) [66] and O3 (FOXO3) [67, 68], nuclear factor κB (NF-κB) [115], Notch1 [95], matrix metalloproteinase (MMP)-14 [92], manganese superoxide dismutase (MnSOD) [65, 87], and c-Jun [13]. …”