Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives

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

Published: Aug. 2, 2023

Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause end-stage renal (ESRD) worldwide. Currently, there are limited therapeutic drugs available for DKD. While previous research has primarily focused on glomerular injury, recent studies have increasingly emphasized role tubular injury in pathogenesis Various factors, including hyperglycemia, lipid accumulation, oxidative stress, hypoxia, RAAS, ER inflammation, EMT programmed cell death, been shown to induce contribute progression Additionally, traditional hypoglycemic drugs, anti-inflammation therapies, anti-senescence mineralocorticoid receptor antagonists, stem therapies demonstrated their potential alleviate This review will provide insights into latest mechanisms treatments

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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Pathological mechanisms of kidney disease in ageing

Nature Reviews Nephrology, Journal Year: 2024, Volume and Issue: 20(9), P. 603 - 615

Published: July 18, 2024

Language: Английский

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The PINK1/PARK2/optineurin pathway of mitophagy is activated for protection in septic acute kidney injury

Redox Biology, Journal Year: 2020, Volume and Issue: 38, P. 101767 - 101767

Published: Oct. 23, 2020

Sepsis is the major cause of acute kidney injury (AKI) associated with high mortality rates. Mitochondrial dysfunction contributes to pathophysiology septic AKI. Mitophagy an important mitochondrial quality control mechanism that selectively eliminates damaged mitochondria, but its role and regulation in AKI remain largely unknown. Here, we demonstrate induction mitophagy mouse models induced by lipopolysaccharide (LPS) treatment or cecal ligation puncture. was also cultured proximal tubular epithelial cells exposed LPS. Induction under these experimental setting suppressed pink1 park2 knockout, indicating PINK1/PARK2 pathway In addition, sepsis more severe cell apoptosis knockout mice than wild-type mice, suggesting a beneficial Furthermore, renal treated LPS, knockdown inhibited accumulation autophagy adaptor optineurin (OPTN) silencing Optn LPS-induced mitophagy. Taken together, findings suggest plays control, survival, function

Language: Английский

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AMPK/mTOR Signaling in Autophagy Regulation During Cisplatin-Induced Acute Kidney Injury

Frontiers in Physiology, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 17, 2020

Autophagy is a conserved, multistep pathway that degrades and recycles dysfunctional organelles macromolecules to maintain cellular homeostasis. Mammalian target of rapamycin (mTOR) adenosine-monophosphate activated-protein kinase (AMPK) are major negative positive regulators autophagy, respectively. In cisplatin-induced acute kidney injury (AKI) or nephrotoxicity, autophagy rapidly induced in renal tubular epithelial cells acts as cytoprotective mechanism for cell survival. Both mTOR AMPK have been implicated the regulation AKI. Targeting and/or may offer effective strategies protection during cisplatin-mediated chemotherapy.

Language: Английский

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Renal plasticity revealed through reversal of polycystic kidney disease in mice

Nature Genetics, Journal Year: 2021, Volume and Issue: 53(12), P. 1649 - 1663

Published: Oct. 11, 2021

Language: Английский

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Value of [68Ga]Ga-FAPI-04 imaging in the diagnosis of renal fibrosis

European Journal of Nuclear Medicine and Molecular Imaging, Journal Year: 2021, Volume and Issue: 48(11), P. 3493 - 3501

Published: April 7, 2021

Language: Английский

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Potential Therapeutic Targets for Cisplatin-Induced Kidney Injury: Lessons from Other Models of AKI and Fibrosis

Journal of the American Society of Nephrology, Journal Year: 2021, Volume and Issue: 32(7), P. 1559 - 1567

Published: May 28, 2021

The effectiveness of cisplatin, a mainstay in the treatment many solid organ cancers, is hindered by dose-limiting nephrotoxicity. Cisplatin causes AKI 30% patients. Patients who do not develop clinical standards during are still at risk for long-term decline kidney function and development CKD. connection between CKD has become increasingly studied, with renal fibrosis hallmark development. To prevent both short- effects researchers must use models that reflect types pathology. Although lot known about cisplatin-induced AKI, very little mechanisms which repeated low levels cisplatin lead to In this review, strategies used various rodent injury, its progression fibrosis, or both, examined gain mechanistic insights identify potential therapeutic targets pathologies. Reviewing results from these highlights diverse highly complex role cell death, senescence, endoplasmic reticulum stress, autophagy, immune activation acute chronic injuries. several injury needed agents will all aspects injury.

Language: Английский

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Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy

Autophagy, Journal Year: 2022, Volume and Issue: 19(2), P. 505 - 524

Published: June 6, 2022

Podocyte injury leading to albuminuria is a characteristic feature of diabetic nephropathy (DN). Hyperglycemia and advanced glycation end products (AGEs) are major determinants DN. However, the underlying mechanisms podocyte remain poorly understood. The cytosolic protein TNFAIP2/M-Sec required for tunneling nanotubes (TNTs) formation, which membrane channels that transiently connect cells, allowing organelle transfer. Podocytes express TNFAIP2 form TNTs, but potential relevance TNFAIP2-TNT system in DN unknown. We studied expression both human experimental renal effect tnfaip2 deletion streptozotocin-induced Moreover, we explored role podocytes exposed diabetes-related insults. was overexpressed by exposre high glucose AGEs induced system. In mice, exacerbated albuminuria, function loss, injury, mesangial expansion. blockade autophagic flux due lysosomal dysfunction observed diabetes-injured vitro vivo deletion. TNTs allowed autophagosome lysosome exchange between podocytes, thereby ameliorating AGE-induced apoptosis. This protective abolished deletion, TNT inhibition, donor cell damage. By contrast, Tnfaip2 overexpression enhanced TNT-mediated transfer prevented autophagy conclusion, plays an important context may represent novel druggable target.Abbreviations: AGEs: products; AKT1: AKT serine/threonine kinase 1; AO: acridine orange; ALs: autolysosomes; APs: autophagosomes; BM: bone marrow; BSA: bovine serum albumin; CTSD: cathepsin D; DIC: differential interference contrast; DN: nephropathy; FSGS: focal segmental glomerulosclerosis; HG: glucose; KO: knockout; LAMP1: lysosomal-associated LMP: permeabilization; MAP1LC3/LC3: microtubule-associated 1 light chain 3; PI3K: phosphoinositide 3-kinase; STZ: streptozotocin; TNF: tumor necrosis factor; TNFAIP2: factor, alpha-induced 2; TNTs: nanotubes; WT: wild type.

Language: Английский

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The mixed blessing of AMPK signaling in Cancer treatments

BMC Cancer, Journal Year: 2022, Volume and Issue: 22(1)

Published: Jan. 25, 2022

Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic biosynthetic demands. A major regulator of cellular energy homeostasis, normal cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation the mechanistic target Rapamycin (mTOR) pathway, specifically, by inhibiting mTOR complex mTORC1, which facilitates proliferation, activating mTORC2 survival. Given conflicting roles, effects activation can be counter intuitive. Prior establishment cancer, acts as a tumor suppressor. However, following onset has been shown either suppress or promote depending on type state.To unravel controversial roles we developed computational model simulate pharmacological maneuvers that key metabolic signalling nodes, with specific focus AMPK, mTORC, their modulators. Specifically, constructed an ordinary differential equation-based AMPK-mTORC signaling, parametrized based existing experimental data.Model simulations were conducted yield predictions: (i) increasing activity opposite mTORC nutrient availability; (ii) indirect inhibition through sirtuin 1 (SIRT1) only effect under conditions low (iii) balance between proliferation survival exhibits intricate dependence DEP domain-containing mTOR-interacting (DEPTOR) abundance activity; (iv) simultaneous direct potential strategy for suppressing both proliferation.Taken together, clarify competing tumorigenesis, may insights innovative therapeutic strategies.

Language: Английский

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