Signaling pathways of chronic kidney diseases, implications for therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 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.

Language: Английский

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The crucial role and mechanism of insulin resistance in metabolic disease

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: March 28, 2023

Insulin resistance (IR) plays a crucial role in the development and progression of metabolism-related diseases such as diabetes, hypertension, tumors, nonalcoholic fatty liver disease, provides basis for common understanding these chronic diseases. In this study, we provide systematic review causes, mechanisms, treatments IR. The pathogenesis IR depends on genetics, obesity, age, drug effects. Mechanistically, any factor leading to abnormalities insulin signaling pathway leads host, including receptor abnormalities, disturbances internal environment (regarding inflammation, hypoxia, lipotoxicity, immunity), metabolic function organelles, other abnormalities. available therapeutic strategies are mainly exercise dietary habit improvement, chemotherapy based biguanides glucagon-like peptide-1, traditional Chinese medicine (e.g., herbs acupuncture) can also be helpful. Based current there still some vacancies follow up consider, is need define more precise biomarkers different lifestyle interventions, explore natural or synthetic drugs targeting treatment. This could enable treatment patients with multiple combined diseases, aim treating disease holistically reduce healthcare expenditures improve quality life extent.

Language: Английский

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Targeting inflammation to treat diabetic kidney disease: the road to 2030

Kidney International, Journal Year: 2022, Volume and Issue: 103(2), P. 282 - 296

Published: Dec. 5, 2022

Language: Английский

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Tubular epithelial cell-to-macrophage communication forms a negative feedback loop via extracellular vesicle transfer to promote renal inflammation and apoptosis in diabetic nephropathy

Theranostics, Journal Year: 2021, Volume and Issue: 12(1), P. 324 - 339

Published: Nov. 10, 2021

Background: Macrophage infiltration around lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN).However, how these two types communicate remains obscure.We previously demonstrated that LRG1 was elevated in the process kidney injury.Here, we macrophage-derived, LRG1-enriched extracellular vesicles (EVs) exacerbated DN.Methods: We induced an experimental T2DM mouse model with HFD diet for four months.Renal primary and macrophage-derived EVs were isolated from T2D mice by differential ultracentrifugation.To investigate whether TEC-derived EV (EVe) activate macrophages, bone marrow-derived macrophages (BMDMs) incubated EVe.To activated (EVm) induce TEC apoptosis, EVm cocultured renal cells.Subsequently, evaluated effect EVe investigating apoptosis mechanism.Results: incubation TECs DN or HK-2 mTECs lysophosphatidyl choline (LPC) increased release EVe.Interestingly, inflammatory phenotype EVm.Furthermore, could injured LPC.Importantly, found leucine-rich α-2-glycoprotein 1 (LRG1)-enriched via TGFβR1-dependent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-enriched death receptor 5 (DR5)-dependent process.Conclusion: Our findings indicated novel cell communication mechanism between DN, which be potential therapeutic target.

Language: Английский

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Ferroptosis as a Novel Therapeutic Target for Diabetes and Its Complications

Frontiers in Endocrinology, Journal Year: 2022, Volume and Issue: 13

Published: March 29, 2022

The global diabetes epidemic and its complications are increasing, thereby posing a major threat to public health. A comprehensive understanding of mellitus (DM) is necessary for the development effective treatments. Ferroptosis newly identified form programmed cell death caused by production reactive oxygen species an imbalance in iron homeostasis. Increasing evidence suggests that ferroptosis plays pivotal role pathogenesis diabetes-related complications. In this review, we summarize potential impact regulatory mechanisms on complications, as well inhibitors diabetic Therefore, developing drugs or agents target may provide new treatment strategies patients with diabetes.

Language: Английский

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Probiotics improve renal function, glucose, lipids, inflammation and oxidative stress in diabetic kidney disease: a systematic review and meta-analysis

Renal Failure, Journal Year: 2022, Volume and Issue: 44(1), P. 862 - 880

Published: May 24, 2022

Aims The role of probiotics in the management diabetic kidney disease (DKD) has been shown. Several current trials are investigating effect probiotics, which widely used to modulate biomarkers renal function, glucose, lipids, inflammation and oxidative stress patients with DKD. However, their findings controversial. This study aimed systematically evaluate impact on DKD via meta-analysis.Methods PubMed, Cochrane Library, Web Science, Scopus, Embase, China National Knowledge Infrastructure, Chinese Wanfang Database VIP were searched for relevant studies from establishment these databases September 2021. pooled results evaluated indicators Additionally, subgroup analysis was performed based intervention duration, probiotic dose consumption patterns, respectively.Results Ten that included 552 participants identified analysis. Compared controls, significantly decreased serum creatinine (Scr) [WMD = −0.17 mg/dL; 95%CI −0.29, −0.05; p 0.004], blood urea nitrogen (BUN) −1.36 −2.20, −0.52; 0.001], cystatin C (Cys C) −29.50 ng/mL; −32.82, −26.18; < 0.00001], urinary albumin/creatinine ratio (UACR) −16.05 mg/g; −27.12, −4.99; 0.004] natrium (Na) −0.94 mmol/L; −1.82, 0.04] Enhanced glycemic control observed receiving compared as demonstrated by reduced levels fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homeostasis model assessment-estimated insulin resistance (HOMA-IR), increased quantitative sensitivity check index (QUICKI). Probiotics affected lipid metabolism parameters decreasing triglycerides (TG), total cholesterol (TC) low-density lipoprotein (LDL-c) could also improve high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), antioxidant capacity (TAC), glutathione (GSH) nitric oxide (NO). showed those who received multiple species had a statistically significant difference BUN, FPG, HOMA-IR, high-density (HDL-c), MDA, TAC, NO. Meanwhile, Scr, LDL-c, HDL-c, TAC ameliorated when duration more than eight weeks MDA improved greater four billion CFU/day.Conclusions Our revealed delay progression function injury, metabolism, reduce Subgroup patterns an outcomes.

Language: Английский

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Podocyte injury of diabetic nephropathy: Novel mechanism discovery and therapeutic prospects

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115670 - 115670

Published: Oct. 13, 2023

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, posing significant challenges in terms early prevention, clinical diagnosis, and treatment. Consequently, it has emerged as major contributor to end-stage renal disease. The glomerular filtration barrier, composed podocytes, endothelial cells, the basement membrane, plays vital role maintaining function. Disruptions podocyte function, including hypertrophy, shedding, reduced density, apoptosis, can impair integrity resulting elevated proteinuria, abnormal rate, increased creatinine levels. Hence, recent research increasingly focused on injury DN, with growing emphasis exploring therapeutic interventions targeting injury. Studies have revealed that factors such lipotoxicity, hemodynamic abnormalities, oxidative stress, mitochondrial dysfunction, impaired autophagy contribute This review aims summarize underlying mechanisms DN provide an overview current status regarding experimental drugs DN. findings presented herein may offer potential targets strategies for management associated

Language: Английский

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Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: Jan. 11, 2024

Abstract The functional and structural changes in the proximal tubule play an important role occurrence development of diabetic kidney disease (DKD). Diabetes-induced metabolic changes, including lipid metabolism reprogramming, are reported to lead state tubular epithelial cells (TECs), among all disturbances metabolism, mitochondria serve as central regulators. Mitochondrial dysfunction, accompanied by increased production mitochondrial reactive oxygen species (mtROS), is considered one primary factors causing injury. Most studies have discussed how altered flux drives oxidative stress during DKD. In present study, we focused on targeting damage upstream factor abnormalities under conditions TECs. Using SS31, a tetrapeptide that protects cristae structure, demonstrated contributes TEC injury peroxidation caused accumulation. Mitochondria protected using SS31 significantly reversed decreased expression key enzymes regulators fatty acid oxidation (FAO), but had no obvious effect major glucose rate-limiting enzymes. facilitated renal Sphingosine-1-phosphate (S1P) deposition limited elevated Acer1, S1pr1 SPHK1 activity, Spns2 expression. These data suggest unbalanced droplet (LD) formulation, peroxidation, impaired FAO sphingolipid homeostasis An vitro study high drove cytosolic phospholipase A2 (cPLA2), which, turn, was responsible for LD generation S1P accumulation, HK-2 cells. A mitochondria-targeted antioxidant inhibited activation cPLA2f isoforms. Taken together, these findings identify mechanistic links between reprogrammed TECs, provide further evidence nephroprotective effects via influencing pathways.

Language: Английский

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Mitochondrial metabolic reprogramming in diabetic kidney disease

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(6)

Published: June 24, 2024

Abstract Diabetic kidney disease, known as a glomerular arises from metabolic disorder impairing renal cell function. Mitochondria, crucial organelles, play key role in substance metabolism via oxidative phosphorylation to generate ATP. Cells undergo reprogramming compensatory mechanism fulfill energy needs for survival and growth, attracting scholarly attention recent years. Studies indicate that mitochondrial significantly influences the pathophysiological progression of DKD. Alterations lead abnormal expression signaling molecules activation pathways, inducing stress-related cellular damage, inflammatory responses, apoptosis, autophagy irregularities, culminating fibrosis insufficiency. This review delves into impact on DKD pathogenesis, emphasizing regulation regulators downstream pathways. Therapeutic interventions targeting can potentially delay progression. The findings underscore importance focusing develop safer more effective therapeutic approaches.

Language: Английский

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Lipophagy deficiency exacerbates ectopic lipid accumulation and tubular cells injury in diabetic nephropathy

Cell Death and Disease, Journal Year: 2021, Volume and Issue: 12(11)

Published: Oct. 30, 2021

Abstract Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but precise mechanism is not fully understood. Whether lipophagy, selective type autophagy participates renal ectopic lipid deposition (ELD) and kidney DN unknown. Here, decreased increased ELD lipotoxcity were observed tubular cells patients with DN, which accompanied reduced expression AdipoR1 p-AMPK. Similar results found db/db mice, these changes reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, significantly level lipophagy was HK-2 cells, human proximal cell line treated high glucose, consistent deposition, apoptosis fibrosis, while partially alleviated AdipoRon. However, effects abolished pretreatment ULK1 inhibitor SBI-0206965, chloroquine enhanced AMPK AICAR. These data suggested first time autophagy-mediated deficiency lipid-related injury DN.

Language: Английский

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