Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment

Kidney International, Год журнала: 2019, Номер 96(5), С. 1083 - 1099

Опубликована: Июнь 8, 2019

Язык: Английский

---

Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance

Theranostics, Год журнала: 2020, Номер 11(4), С. 1845 - 1863

Опубликована: Дек. 16, 2020

Aims: Ischemia-reperfusion injury (IRI)-induced acute kidney (IRI-AKI) is characterized by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation, but the potential link among these features remains unclear. In this study, we aimed to investigate specific role ROS (mtROS) in initiating DNA (mtDNA) damage inflammation during IRI-AKI. Methods: The changes renal function, IRI-AKI mice with or without mtROS inhibition were analyzed vivo. impact on TFAM (mitochondrial transcription factor A), Lon protease, mtDNA, respiration, cytokine release was tubular cells vitro. effects knockdown also Finally, mtDNA nucleoids measured samples from patients. Results: Decreasing attenuated damage, mice. reversed decrease copy number that occurs HK2 under oxidative stress. reduced abundance suppressing its promoting Lon-mediated degradation. Silencing abolished Mito-Tempo (MT)-induced rescue function Loss found kidneys AKI Conclusion: can promote TFAM-mediated maintenance, resulting decreased energy metabolism increased release. defects may be a promising target for repair after

Язык: Английский

---

The sirtuin family in health and disease

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Дек. 29, 2022

Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, involved numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles members SIRT family health disease conditions. Notably, this protein plays a variety important cellular biology such as inflammation, metabolism, oxidative stress, apoptosis, etc., thus, it is considered potential therapeutic target for different kinds pathologies including cancer, cardiovascular disease, respiratory other Moreover, identification modulators exploring functions these prompted increased efforts discover new small molecules, which can modify activity. Furthermore, several randomized controlled trials indicated that interventions might affect expression human samples, supplementation diverse impact on physiological function participants. In review, we introduce history structure family, discuss molecular mechanisms elaborate regulatory SIRTs summarize inhibitors activators, review related clinical studies.

Язык: Английский

---

Mitochondrial quality control in kidney injury and repair

Nature Reviews Nephrology, Год журнала: 2020, Номер 17(5), С. 299 - 318

Опубликована: Ноя. 24, 2020

Язык: Английский

---

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

---

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(7), С. 2632 - 2632

Опубликована: Апрель 10, 2020

Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. mainly associated with dysfunctional signaling and insulin resistance response non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, kidney. Serum lipid abnormalities renal have been development kidney diseases, particular diabetic nephropathy. Chronic hyperinsulinemia, often seen type 2 diabetes, plays a crucial role blood liver metabolism abnormalities, thus resulting increased non-esterified fatty acids (NEFA). Excessive alters cellular homeostasis activates lipogenic glycogenic cell-signaling pathways. Recent evidences indicate that both quantity quality are involved damage to lipotoxicity activating inflammation, oxidative stress, mitochondrial dysfunction, cell-death. The pathological effects observed cells, promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, formation macrophage-derived foam cells. Therefore, this review examines recent preclinical clinical research about potentially harmful kidney, metabolic markers these mechanisms, major pathways affected, causes excessive accumulation, types involved, well offers comprehensive update therapeutic strategies targeting lipotoxicity.

Язык: Английский

---

Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Mitochondrial Damage and Inflammation by Stabilizing Mitochondrial DNA

ACS Nano, Год журнала: 2020, Номер 15(1), С. 1519 - 1538

Опубликована: Дек. 28, 2020

Mitochondrial dysfunction is a key feature of injury to numerous tissues and stem cell aging. Although the tissue regenerative role mesenchymal (MSC)-derived extracellular vesicles (MSC-EVs) well known, their specific in regulating mitochondrial function target cells remains elusive. Here, we report that MSC-EVs attenuated mtDNA damage inflammation after acute kidney (AKI) this effect was at least partially dependent on transcription factor A (TFAM) pathway. In detail, TFAM were depleted by oxidative stress MSCs from aged or diabetic donors. Higher levels mRNA detected normal control (NC) than TFAM-knockdown (TFAM-KD) EVs. EV-mediated transfer recipient unaffected transcriptional inhibition. Accordingly, application restored protein TFAM-mtDNA complex (nucleoid) stability, thereby reversing deletion phosphorylation (OXPHOS) defects injured renal tubular cells. Loss also led downregulation multiple anti-inflammatory miRNAs proteins MSC-EVs. vivo, intravenously injected EVs primarily accumulated liver, kidney, spleen, lung. lesion formation, damage, mice with AKI, whereas TFAM-KD resulted poor therapeutic outcomes. Moreover, overexpression (TFAM-OE) improved rescue some extent. This study suggests are promising nanotherapeutics for diseases characterized signaling essential maintaining capacity.

Язык: Английский

---

Signaling pathways of chronic kidney diseases, implications for therapeutics

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Июнь 9, 2022

Abstract Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity oxidative stress are the driving force for loss of including tubules, glomerulus, endothelium. NLRP3 inflammasome signaling, MAPK PI3K/Akt RAAS signaling involves in lipotoxicity. The upregulated Nox expression decreased Nrf2 result directly. injured resident cells release proinflammatory cytokines chemokines to recruit immune such as macrophages from bone marrow. NF-κB JAK-STAT Toll-like receptor cGAS-STING major pathways mediate inflammation inflammatory cells. produce secret great number profibrotic TGF-β1, Wnt ligands, angiotensin II. TGF-β Notch evoke activation promote generation ECM. potential therapies targeted these also introduced here. In this review, we update key lipotoxicity, stress, kidneys with injury, drugs based on latest studies. Unifying will be instrumental advance further basic clinical investigation CKD.

Язык: Английский

---

Extracellular vesicle–encapsulated IL-10 as novel nanotherapeutics against ischemic AKI

Science Advances, Год журнала: 2020, Номер 6(33)

Опубликована: Авг. 12, 2020

Recently, extracellular vesicles (EVs) have been attracting strong research interest for use as natural drug delivery systems. We report an approach to manufacturing interleukin-10 (IL-10)-loaded EVs (IL-10+ EVs) by engineering macrophages treating ischemic acute kidney injury (AKI). Delivery of IL-10 via enhanced not only the stability IL-10, but also its targeting due adhesive components on EV surface. Treatment with IL-10+ significantly ameliorated renal tubular and inflammation caused ischemia/reperfusion injury, potently prevented transition chronic disease. Mechanistically, targeted epithelial cells, suppressed mammalian target rapamycin signaling, thereby promoting mitophagy maintain mitochondrial fitness. Moreover, efficiently drove M2 macrophage polarization in tubulointerstitium. Our study demonstrates that can serve a promising platform manipulate effective treatment AKI.

Язык: Английский

---

Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection

Nature Reviews Nephrology, Год журнала: 2021, Номер 17(5), С. 335 - 349

Опубликована: Фев. 5, 2021

Язык: Английский

---