Sirtuin 3 Activation by Honokiol Decreases Unilateral Ureteral Obstruction-Induced Renal Inflammation and Fibrosis via Regulation of Mitochondrial Dynamics and the Renal NF-κB-TGF-β1/Smad Signaling Pathway

Abstract

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3 (SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrial biogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as a pharmaceutical SIRT3 activator, has been observed to have a protective effect against pressure overload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigated whether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation of mitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubular injury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKL treatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusion through SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might have beneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation of mitochondrial dynamics and the NF-κB/TGF-β1/Smad signaling pathway.

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

“…For instance, Honokiol is one of the most studied SIRT3 activators and is a natural lignan derived from the bark of Magnolia. Honokiol could increase SIRT3 expression and deacetylation activity, which have a favorable effect on heart disease 16 , 137 , renal disease 173 , surgery/anesthesia-induced cognitive decline 174 and Vitiligo 175 . For heart disease, Honokiol activation of SIRT3 further decreases the acetylation levels of MnSOD2 and OSCP, resulting in improved mitochondrial rate of oxygen consumption and inhibition of ROS synthesis.…”

“…This makes it possible for Honokiol to contribute to adjuvant therapy of chemotherapy 137 . In renal disease, Honokiol stimulates SIRT3 activity to block the NF-κB-TGF- β1/Smad regulated inflammation and fibrosis signaling in renal fibrosis mice model 173 . Surprisingly, Honokiol can ameliorate surgery-induced or anesthesia-induced cognitive decline in mice via SIRT3 activation mediating ROS elimination and apoptosis inhibition 174 .…”

Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

“…Indeed, it has been shown that Honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol, HKL) is able to stimulate the activity of Sirtuin 3 (SIRT3), which sequentially mediates the activation of OPA1 and decreases DRP1 expression, restoring the correct mitochondrial fusion and fission dynamics and normal mitochondrial shape and function. Thus, targeting mitochondrial dynamics can be a novel therapeutic approach for the treatment of acute or chronic kidney diseases [ 31 ].…”

Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction

“…In the same way, sirtuin 3 (SIRT3) is a deacetylase protein mainly localized in mitochondria, involved in the regulation of mitochondrial biogenesis and dynamics 95,96 . SIRT3 protein levels are decreased in UUO‐OKs 92 . Meanwhile, the upregulation of SIRT3 expression in UUO‐OKs helps to reduce mitochondrial fragmentation since SIRT3 activates Opa1 92 .…”