Diabetic Nephropathy: Update on Pillars of Therapy Slowing Progression

Diabetes Care, Journal Year: 2023, Volume and Issue: 46(9), P. 1574 - 1586

Published: Aug. 25, 2023

Management of diabetic kidney disease (DKD) has evolved in parallel with our growing understanding the multiple interrelated pathophysiological mechanisms that involve hemodynamic, metabolic, and inflammatory pathways. These pathways others play a vital role initiation progression DKD. Since its initial discovery, blockade renin-angiotensin system remained cornerstone DKD management, leaving large component residual risk to be dealt with. The advent sodium-glucose cotransporter 2 inhibitors followed by nonsteroidal mineralocorticoid receptor antagonists and, some extent, glucagon-like peptide 1 agonists (GLP-1 RAs) ushered resounding paradigm shift supports pillared approach maximizing treatment reduce outcomes. This is like derived from heart failure treatment. mandates all agents have been shown clinical trials cardiovascular outcomes and/or mortality greater extent than single drug class alone should used combination. In this way, each focuses on specific aspect disease's pathophysiology. Thus, failure, β-blockers, sacubitril/valsartan, antagonist, diuretic are together. article, we review evolution pillar concept therapy as it applies discuss how based outcome evidence. We also exciting possibility GLP-1 RAs may an additional quest further slow diabetes.

Language: Английский

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Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3219 - 3219

Published: Feb. 6, 2023

Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, enzymatic activity. Ubiquitin-specific proteases (USPs) constitute largest deubiquitinating enzyme family. To date, accumulating evidence indicates several USPs positively negatively affect metabolic diseases. USP22 in pancreatic β-cells, USP2 adipose tissue macrophages, USP9X, 20, 33 myocytes, USP4, 7, 10, 18 hepatocytes, hypothalamus improve hyperglycemia, whereas USP19 adipocytes, USP21 USP2, 14, 20 hepatocytes promote hyperglycemia. In contrast, USP1, 5, 9X, 15, 22, 36, 48 modulate progression diabetic nephropathy, neuropathy, and/or retinopathy. ameliorates non-alcoholic fatty liver disease (NAFLD), while hepatic 11, 19, exacerbate it. The roles USP7 22 disorders controversial. 17, vascular cells postulated to be determinants atherosclerosis. Moreover, mutations

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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Pericyte Loss in Diseases

Cells, Journal Year: 2023, Volume and Issue: 12(15), P. 1931 - 1931

Published: July 26, 2023

Pericytes are specialized cells located in close proximity to endothelial within the microvasculature. They play a crucial role regulating blood flow, stabilizing vessel walls, and maintaining integrity of blood–brain barrier. The loss pericytes has been associated with development progression various diseases, such as diabetes, Alzheimer’s disease, sepsis, stroke, traumatic brain injury. This review examines detection pericyte different explores methods employed assess coverage, elucidates potential mechanisms contributing these pathological conditions. Additionally, current therapeutic strategies targeting discussed, along future interventions aimed at preserving function promoting disease mitigation.

Language: Английский

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Research progress on multiple cell death pathways of podocytes in diabetic kidney disease

Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(1)

Published: Oct. 12, 2023

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration rate, failure. The injury death podocytes keys to DKD. Currently, a variety cell modes have been identified in podocytes, including apoptosis, autophagy, endoplasmic reticulum (ER) stress, pyroptosis, necroptosis, ferroptosis, mitotic catastrophe, etc. signaling pathways leading these processes interconnected can be activated simultaneously or parallel. They essential for survival that determine fate cells. With deepening research on mechanism death, more researchers devoted their attention underlying pathologic drug therapy In this paper, we discussed podocyte physiologic role DKD processes. We also provide an overview types specific mechanisms involved each type DKD, as well related targeted methods drugs reviewed. last part discuss complexity potential crosstalk between various which will help improve understanding lay foundation new ideal strategies treatment future.

Language: Английский

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The cGAS-STING pathway: a therapeutic target in diabetes and its complications

Burns & Trauma, Journal Year: 2024, Volume and Issue: 12

Published: Jan. 1, 2024

Diabetic wound healing (DWH) represents a major complication of diabetes where inflammation is key impediment to proper healing. The cyclic GMP-AMP synthase (cGAS)-stimulator interferon genes (STING) signaling pathway has emerged as central mediator inflammatory responses cell stress and damage. However, the contribution cGAS-STING activation impaired in DWH remains understudied. In this review, we examine evidence that cGAS-STING-driven critical factor underlying defective DWH. We summarize studies revealing upregulation diabetic wounds discuss how exacerbates senescence disrupts cellular metabolism block Partial pharmaceutical inhibition shown promise damping improving preclinical models. highlight knowledge gaps regarding DWH, including its relationships with endoplasmic reticulum metal-ion signaling. Elucidating these mechanisms may unveil new therapeutic targets within improve outcomes This review synthesizes current understanding contributes pathology proposes future research directions exploit modulation for benefit.

Language: Английский

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Pharmacological functions of salidroside in renal diseases: facts and perspectives

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

Rhodiola rosea is a valuable functional medicinal plant widely utilized in China and other Asian countries for its anti-fatigue, anti-aging, altitude sickness prevention properties. Salidroside, most active constituent derived from , exhibits potent antioxidative, hypoxia-resistant, anti-inflammatory, anticancer, anti-aging effects that have garnered significant attention. The appreciation of the pharmacological role salidroside has burgeoned over last decade, making it beneficial option treatment multiple diseases, including atherosclerosis, Alzheimer’s disease, Parkinson’s cardiovascular more. With renoprotective effects, parallel with inhibition oxidative stress inflammation, holds promise as potential therapeutic agent kidney damage. This article provides an overview microinflammatory state disease discuss current strategies, particular focus on highlighting recent advancements utilizing renal disease. mechanisms action are primarily associated regulation gene protein expression glomerular endothelial cells, podocytes, tubule mesangial cells cell carcinoma cell, TNF-α, TGF-β, IL-1β, IL-17A, IL-6, MCP-1, Bcl-2, VEGF, ECM protein, caspase-3, HIF-1α, BIM, well modulation AMPK/SIRT1, Nrf2/HO-1, Sirt1/PGC-1α, ROS/Src/Cav-1, Akt/GSK-3β, TXNIP-NLRP3, ERK1/2, TGF-β1/Smad2/3, PI3K/Akt, Wnt1/Wnt3a β-catenin, TLR4/NF-κB, MAPK, JAK2/STAT3, SIRT1/Nrf2 pathways. To best our knowledge, this review first to comprehensively cover protective diverse suggests great be developed drug metabolic syndrome, cerebrovascular diseases complications.

Language: Английский

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The redox-sensitive GSK3β is a key regulator of glomerular podocyte injury in type 2 diabetic kidney disease

Redox Biology, Journal Year: 2024, Volume and Issue: 72, P. 103127 - 103127

Published: March 16, 2024

Emerging evidence suggests that GSK3β, a redox-sensitive transducer downstream of insulin signaling, acts as convergent point for myriad pathways implicated in kidney injury, repair, and regeneration. However, its role diabetic disease remains controversial. In cultured glomerular podocytes, exposure to milieu type 2 diabetes elicited prominent signs podocyte injury degeneration, marked by loss homeostatic marker proteins like synaptopodin, actin cytoskeleton disruption, oxidative stress apoptosis, stress-induced premature senescence, shown increased staining senescence-associated β-galactosidase activity, amplified formation γH2AX foci, elevated expression mediators senescence p21 p16INK4A. These degenerative changes coincided with GSK3β hyperactivity, evidenced overexpression reduced inhibitory phosphorylation were averted tideglusib, highly-selective small molecule inhibitor GSK3β. agreement, post-hoc analysis publicly-available transcriptomics dataset from patients nephropathy revealed the curated nephropathy-related gene set was enriched high group. Mechanistically, GSK3β-modulated nuclear factor Nrf2 signaling is involved podocytopathy, because knockdown reinforced antioxidant response suppressed stress, resulting an improvement senescence. Conversely, ectopic constitutively active mutant impaired augmented culminating exacerbated Moreover, IRS-1 found be cognate substrate at IRS-1S332, which negatively regulates activity. hyperactivity promoted phosphorylation, denoting desensitized signaling. Consistently, vivo db/db mice nephropathy, hyperactive associated hyperphosphorylation, Our finding likely novel therapeutic target treating injury.

Language: Английский

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Sirt6 overexpression relieves ferroptosis and delays the progression of diabetic nephropathy via Nrf2/GPX4 pathway

Renal Failure, Journal Year: 2024, Volume and Issue: 46(2)

Published: July 31, 2024

Objective Sirt6, reactive oxygen species and ferroptosis may participate in the pathogenesis of Diabetic Nephropathy (DN). Exploring relationship between oxidative stress, provides new scientific ideas to DN.

Language: Английский

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Phenylsulfate-induced oxidative stress and mitochondrial dysfunction in podocytes are ameliorated by Astragaloside IV activation of the SIRT1/PGC1α /Nrf1 signaling pathway

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 177, P. 117008 - 117008

Published: June 19, 2024

Astragaloside IV (AS-IV) exhibits diverse biological activities. Despite this, the detailed molecular mechanisms by which AS-IV ameliorates diabetic nephropathy (DN) and shields podocytes from oxidative stress (OS) mitochondrial dysfunction remain poorly understood. In this study, we used biochemical assays, histopathological analysis, Doppler ultrasound, transmission electron microscopy，flow cytometry, fluorescence staining, Western blotting other methods. was administered to db/db mice for in vivo experimentation. Our findings indicated that treatment significantly reduced diabetes-associated markers, proteinuria, kidney damage. It also diminished ROS levels kidney, enhanced expression of endogenous antioxidant enzymes, improved health. Phenyl sulfate (PS), a protein-bound uremic solute enteric origin, has been closely linked with DN represents promising avenue further research. vitro, PS exposure induced OS podocytes, increasing while decreasing enzyme activity (Catalase, Heme Oxygenase-1, Superoxide Dismutase, Glutathione Peroxidase). inhibitors (N-acetyl-L-cysteine, NAC) as positive control group can reduce restore enzymes protein levels. Additionally, markers associated biosynthesis function (SIRT1, PGC1α, Nrf1, TFAM). These adverse effects were partially reversed treatment. However, co-treatment SIRT1 inhibitor EX527 failed these indicators. Overall, our study demonstrates effectively attenuates mitigates PS-induced via SIRT1/PGC1α/Nrf1 pathway.

Language: Английский

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