Kidney fibrosis: from mechanisms to therapeutic medicines

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Март 17, 2023

Abstract Chronic kidney disease (CKD) is estimated to affect 10–14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading scarring, a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. fibrosis identified tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, vascular rarefaction. Fibrotic niche, where organ initiates, complex interplay between injured parenchyma (like tubular cells) multiple non-parenchymal cell lineages (immune mesenchymal located spatially within scarring areas. Although the mechanisms are complicated due kinds cells involved, with help single-cell technology, many key questions have been explored, such as what kind renal tubules profibrotic, myofibroblasts originate, which immune how communicate each other. In addition, genetics epigenetics deeper that regulate fibrosis. And reversible nature epigenetic changes including DNA methylation, RNA interference, chromatin remodeling, gives an opportunity stop or reverse therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) developed delay progression recent years. Furthermore, better understanding also favored discover biomarkers fibrotic injury. review, we update advances mechanism summarize novel treatment for CKD.

Язык: Английский

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Sirtuins in Renal Health and Disease

Journal of the American Society of Nephrology, Год журнала: 2018, Номер 29(7), С. 1799 - 1809

Опубликована: Апрель 30, 2018

Sirtuins belong to an evolutionarily conserved family of NAD + -dependent deacetylases that share multiple cellular functions related proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammalians express seven sirtuins (SIRT1–7) are localized in different subcellular compartments. Changes sirtuin expression critical several diseases, including metabolic syndrome, diabetes, cancer, aging. In the kidney, most widely studied is SIRT1, which exerts cytoprotective effects by inhibiting cell apoptosis, inflammation, fibrosis together with SIRT3, a crucial sensor regulates ATP generation adaptive response stress. Here, we provide overview biologic molecular targets thereof regulating renal physiology. This review also details progress made understanding effect pathophysiology chronic acute kidney highlighting key role now SIRT6 as potential therapeutic targets. this context, current pharmacologic approaches enhancing activity SIRT1 SIRT3 will be discussed.

Язык: Английский

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Sirtuins in kidney health and disease

Nature Reviews Nephrology, Год журнала: 2024, Номер 20(5), С. 313 - 329

Опубликована: Фев. 6, 2024

Язык: Английский

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Sirt3 modulates fatty acid oxidation and attenuates cisplatin‐induced AKI in mice

Journal of Cellular and Molecular Medicine, Год журнала: 2020, Номер 24(9), С. 5109 - 5121

Опубликована: Апрель 12, 2020

Abstract Fatty acid oxidation (FAO) dysfunction is one of the important mechanisms renal fibrosis. Sirtuin 3 (Sirt3) has been confirmed to alleviate acute kidney injury (AKI) by improving mitochondrial function and participate in regulation FAO other disease models. However, it not clear whether Sirt3 involved regulating improve prognosis AKI induced cisplatin. Here, using a murine model cisplatin‐induced AKI, we revealed that there were significantly extensive lipid deposition mice with AKI. Metabolomics analysis suggested reprogrammed energy metabolism decreased ATP production. In addition, fatty can increase reactive oxygen species (ROS) production induce apoptosis. Our data deletion aggravated dysfunction, resulting increased apoptosis tissues injury. The activation honokiol could reduced wide‐type mice, but Sirt3‐defective mice. We concluded may regulate deacetylating liver kinase B1 activating AMP‐activated protein kinase. Also, as well ROS peroxidation through function. Collectively, these results provide new evidence protective against Enhancing be potential strategy prevent future.

Язык: Английский

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

CNS Neuroscience & Therapeutics, Год журнала: 2018, Номер 25(3), С. 355 - 366

Опубликована: Сен. 17, 2018

Increasing evidence indicates that neuroinflammatory and oxidative stress play two pivotal roles in cognitive impairment after surgery. Honokiol (HNK), as an activator of Sirtuin3 (SIRT3), has potential multiple biological functions. The aim these experiments is to evaluate the effects HNK on surgery/anesthesia-induced decline mice.Adult C57BL/6 mice received a laparotomy under sevoflurane anesthesia or SIRT3 inhibitor (3-TYP) treatment. Cognitive function locomotor activity were evaluated using fear conditioning test open field postoperative 1 3 days. Neuronal apoptosis CA1 CA3 area hippocampus was examined TUNEL assay. And Western blot applied measure expression pro-inflammatory cytokines SIRT3/SOD2 signaling-associated proteins hippocampus. Meanwhile, positive cells calculated by immunohistochemistry. mitochondrial membrane potential, malondialdehyde (MDA), radical oxygen species (mtROS) detected standard methods.Honokiol attenuated surgery-induced memory loss neuronal apoptosis, decreased response, ameliorated damage Notably, surgery/anesthesia induced obviously decrease hippocampal expression, whereas increased thus acetylation superoxide dismutase 2 (SOD2). However, 3-TYP treatment inhibited HNK's rescuing effects.These results suggested activation honokiol may attenuate through regulation

Язык: Английский

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Sirtuin 7 mitigates renal ferroptosis, fibrosis and injury in hypertensive mice by facilitating the KLF15/Nrf2 signaling

Free Radical Biology and Medicine, Год журнала: 2022, Номер 193, С. 459 - 473

Опубликована: Ноя. 1, 2022

Язык: Английский

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SIRT3/6: an amazing challenge and opportunity in the fight against fibrosis and aging

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Янв. 31, 2024

Abstract Fibrosis is a typical aging-related pathological process involving almost all organs, including the heart, kidney, liver, lung, and skin. Fibrogenesis highly orchestrated defined by sequences of cellular response molecular signals mechanisms underlying disease. In pathophysiologic conditions associated with organ fibrosis, variety injurious stimuli such as metabolic disorders, epigenetic changes, aging may induce progression fibrosis. Sirtuins protein kind deacetylase which can regulate cell metabolism participate in physiological functions. this review, we outline our current understanding common principles fibrogenic functional role SIRT3/6 addition, novel protective strategies have been identified directly or indirectly according to these mechanisms. Here, highlight biological function focus on well their inhibitors activators preventative therapeutic interventions for tissue Graphical abstract

Язык: Английский

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Manipulating Sirtuin 3 pathway ameliorates renal damage in experimental diabetes

Scientific Reports, Год журнала: 2020, Номер 10(1)

Опубликована: Май 21, 2020

Abstract More effective treatments for diabetic nephropathy remain a major unmet clinical need. Increased oxidative stress is one of the most important pathological mechanisms that lead to kidney damage and functional impairment induced by diabetes. Sirtuin 3 (SIRT3) main mitochondrial deacetylase critically regulates cellular reactive oxygen species (ROS) production detoxification. Honokiol natural biphenolic compound that, activating SIRT3, can carry out anti-oxidant, anti-inflammatory anti-fibrotic activities. Here, we sought investigate renoprotective effects honokiol in BTBR ob/ob mice with type 2 Diabetic were treated vehicle or between ages 8 14 weeks. Wild-type served as controls. Renal Sirt3 expression was significantly reduced mice, this associated reduction its activity increased ROS levels. Selective activation SIRT3 through administration translated into attenuation albuminuria, amelioration glomerular damage, podocyte injury. preserved wellness SOD2 restoration PGC-1α cells. Additionally, protective role changes enhanced tubular upregulated renal Nampt levels, indicating possible tubule-glomerulus retrograde interplay, which resulted improved activity. Our results demonstrate hitherto unknown effect against disease suggest pharmacological modulation novel approach treating nephropathy.

Язык: Английский

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Targeting energy pathways in kidney disease: the roles of sirtuins, AMPK, and PGC1α

Kidney International, Год журнала: 2020, Номер 99(4), С. 828 - 840

Опубликована: Дек. 8, 2020

Язык: Английский

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Melatonin Alleviates Contrast-Induced Acute Kidney Injury by Activation of Sirt3

Oxidative Medicine and Cellular Longevity, Год журнала: 2021, Номер 2021(1)

Опубликована: Янв. 1, 2021

Oxidative stress and apoptosis play a vital role in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). The purpose our study was to investigate protective effects mechanisms melatonin against CI-AKI mouse model NRK-52E cells. We established mice, animals were pretreated with (20 mg/kg). Our results demonstrated that treatment exerted renoprotective effect by decreasing level serum creatinine (SCr) blood urea nitrogen (BUN), lessening histological changes renal tubular injuries, reducing expression neutrophil gelatinase-associated lipid (NGAL), marker injury. also found pretreatment remarkably increased Sirt3 decreased ac-SOD2 K68 level. Consequently, significantly oxidative Nox4, ROS, malondialdehyde (MDA) content increasing superoxide dismutase (SOD) glutathione peroxidase (GSH-Px) activity levels. antiapoptotic on revealed ratio Bax/Bcl2 cleaved caspase3 number apoptosis-positive In addition, reduced inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), transforming growth β (TGFβ) vivo vitro. deletion specific siRNA abolished above mice iohexol-induced Thus, exhibited antioxidative stress, antiapoptosis, anti-inflammation activation Melatonin may be potential drug ameliorate clinical practice.

Язык: Английский

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