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Matrine alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial dysfunction and inflammation via SIRT3/OPA1 pathway.

ABSTRACT: Cisplatin is extensively used to treat malignancies. However, its clinical use is always limited due to the serious side effects, especially the nephrotoxicity. Matrine (MAT), a tetracyclic quinolizine alkaloid found in sophora genus, exerts multiple pharmacological roles, including anti-oxidative stress, anti-inflammation and anti-apoptosis, but the role of MAT on acute kidney injury (AKI) has not been evaluated. Here, we found that MAT potently inhibited cell injury induced by cisplatin in HK2 cells in vitro, which was associated with the inhibition of oxidative injury and NF-κB-mediated inflammation. Moreover, MAT treatment could activate the SIRT3/OPA1 axis and subsequently suppress the mitochondrial fragmentation and improve mitochondrial function. More importantly, SIRT3 knockdown suppressed the deacetylation of OPA1, which blocked the protective role of MAT on cisplatin-induced cell injury. In vivo, MAT treatment alleviated renal dysfunction, histological damage and inflammation induced by cisplatin in mice. Furthermore, consistent with the founding in vitro, MAT also activated SIRT3-mediated deacetylation of OPA1 and alleviated mitochondrial dysfunction in AKI mice. Our study proved that MAT protected against cisplatin-induced AKI by synergic anti-oxidative stress and anti-inflammation actions via SIRT3/OPA1-mediated improvement of mitochondrial function, suggesting that MAT may be a novel and effective strategy for AKI.

SUBMITTER: Yuan L

PROVIDER: S-EPMC9258713 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale: Sepsis is a severe clinical syndrome featured through organ dysfunction due to infection, while the accompanying acute kidney injury (AKI) is linked to significant incidence of morbidity as well as mortality. Recently, emerging evidence has revealed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is implicated in various renal diseases, while its role and modulation in septic acute kidney injury (S-AKI) remains largely unknown. Methods:In vivo, S-AKI in wild-type and renal tubular epithelial cell (RTEC)-specific NOX4 knockout mice was induced by lipopolysaccharides (LPS) injection or cecal ligation and puncture (CLP). In vitro, TCMK-1 (mouse kidney tubular epithelium cell line) cells were treated with LPS. Serum and supernatant biochemical, mitochondrial dysfunctional, inflammatory and apoptotic parameters were measured and compared across groups. The activation of reactive oxygen species (ROS) and NF-κB signaling was also assessed. Results: NOX4 was predominantly upregulated in RTECs of S-AKI mouse model induced by LPS/CLP and cultured TCMK-1 cells exposed to LPS. RTEC-specific deletion of NOX4 or pharmacological inhibition of NOX4 by GKT137831 both alleviated LPS/CLP-injured renal function and pathology in mice. Furthermore, NOX4 inhibition alleviated mitochondrial dysfunction supported by ultrastructural damage, reduction of ATP production and mitochondrial dynamics imbalance, together with inflammation and apoptosis in kidney injured by LPS/CLP and TCMK-1 cells injured by LPS, while NOX4 overexpression aggravated the above-mentioned indices in TCMK-1 cells with LPS stimulation. Mechanism-wise, the raised NOX4 in RTECs may induce ROS and NF-κB signaling activation in S-AKI. Conclusions: Collectively, genetic or pharmacological inhibition of NOX4 protects from S-AKI by reducing generation of ROS and activation of NF-κB signal, which suppress mitochondrial dysfunction, inflammation together with apoptosis. NOX4 may act as a novel target for the S-AKI therapy.

Project description:RationaleHypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level.ObjectiveWe hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension, but increased Sirt3 protects vascular function and decreases hypertension.Methods and resultsTo test the therapeutic potential of targeting Sirt3 expression, we developed new transgenic mice with global Sirt3OX (Sirt3 overexpression), which protects from endothelial dysfunction, vascular oxidative stress, and hypertrophy and attenuates Ang II (angiotensin II) and deoxycorticosterone acetate-salt induced hypertension. Global Sirt3 depletion in Sirt3-/- mice results in oxidative stress due to hyperacetylation of mitochondrial superoxide dismutase (SOD2), increases HIF1α (hypoxia-inducible factor-1), reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM [vascular cell adhesion molecule-1], ICAM [intercellular adhesion molecule-1], and MCP1 [monocyte chemoattractant protein 1]), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3-dependent 3-fold increases in SOD2 acetylation, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, VCAM, ICAM, and MCP1 levels in hypertensive subjects compared with normotensive subjects.ConclusionsWe suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation, and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.

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Matrine alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial dysfunction and inflammation via SIRT3/OPA1 pathway.

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