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1.
Pharmaceutics ; 15(5)2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37242602

RESUMO

Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of end-stage renal disease. Abnormal lipid metabolism and intrarenal accumulation of lipids have been shown to be strongly correlated with the development and progression of diabetic kidney disease (DKD). Cholesterol, phospholipids, triglycerides, fatty acids, and sphingolipids are among the lipids that are altered in DKD, and their renal accumulation has been linked to the pathogenesis of the disease. In addition, NADPH oxidase-induced production of reactive oxygen species (ROS) plays a critical role in the development of DKD. Several types of lipids have been found to be tightly linked to NADPH oxidase-induced ROS production. This review aims to explore the interplay between lipids and NADPH oxidases in order to provide new insights into the pathogenesis of DKD and identify more effective targeted therapies for the disease.

2.
Pharmaceutics ; 15(3)2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36986825

RESUMO

Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic interventions. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a promising class of drugs, with evidence demonstrating that they can improve renal outcomes in people with diabetes. However, the exact mechanism by which SGLT2i exert their renoprotective effects is not yet fully understood. This study demonstrates that dapagliflozin treatment attenuates renal injury observed in type 2 diabetic mice. This is evidenced by the reduction in renal hypertrophy and proteinuria. Furthermore, dapagliflozin decreases tubulointerstitial fibrosis and glomerulosclerosis by mitigating the generation of reactive oxygen species and inflammation, which are activated through the production of CYP4A-induced 20-HETE. Our findings provide insights onto a novel mechanistic pathway by which SGLT2i exerts their renoprotective effects. Overall, and to our knowledge, the study provides critical insights into the pathophysiology of DKD and represents an important step towards improving outcomes for people with this devastating condition.

3.
Antioxid Redox Signal ; 37(10-12): 802-819, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34544257

RESUMO

Significance: Despite the many efforts put into understanding diabetic nephropathy (DN), direct treatments for DN have yet to be discovered. Understanding the mechanisms behind DN is an essential step in the development of novel therapeutic regimens. The mammalian target of rapamycin (mTOR) pathway has emerged as an important candidate in the quest for drug discovery because of its role in regulating growth, proliferation, as well as protein and lipid metabolism. Recent Advances: Kidney cells have been found to rely on basal autophagy for survival and for conserving kidney integrity. Recent studies have shown that diabetes induces renal autophagy deregulation, leading to kidney injury. Hyper-activation of the mTOR pathway and oxidative stress have been suggested to play a role in diabetes-induced autophagy imbalance. Critical Issues: A detailed understanding of the role of mTOR signaling in diabetes-associated complications is of major importance in the search for a cure. In this review, we provide evidence that mTOR is heavily implicated in diabetes-induced kidney injury. We suggest possible mechanisms through which mTOR exerts its negative effects by increasing insulin resistance, upregulating oxidative stress, and inhibiting autophagy. Future Directions: Both increased oxidative stress and autophagy deregulation are deeply embedded in DN. However, the mechanisms controlling oxidative stress and autophagy are not well understood. Although Akt/mTOR signaling seems to play an important role in oxidative stress and autophagy, further investigation is required to uncover the details of this signaling pathway. Antioxid. Redox Signal. 37, 802-819.


Assuntos
Nefropatias Diabéticas , Serina-Treonina Quinases TOR , Autofagia , Nefropatias Diabéticas/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
4.
Clin Sci (Lond) ; 134(4): 403-417, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32095833

RESUMO

Diabetic kidney disease is one of the most serious complications of diabetes worldwide and is the leading cause of end-stage renal disease. While research has primarily focused on hyperglycemia as a key player in the pathophysiology of diabetic complications, recently, increasing evidence have underlined the role of adipose inflammation in modulating the development and/or progression of diabetic kidney disease. This review focuses on how adipose inflammation contribute to diabetic kidney disease. Furthermore, it discusses in detail the underlying mechanisms of adipose inflammation, including pro-inflammatory cytokines, oxidative stress, and AMPK/mTOR signaling pathway and critically describes their role in diabetic kidney disease. This in-depth understanding of adipose inflammation and its impact on diabetic kidney disease highlights the need for novel interventions in the treatment of diabetic complications.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/patologia , Inflamação/patologia , Rim/lesões , NADPH Oxidase 4/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Humanos
5.
Am J Physiol Renal Physiol ; 315(3): F572-F582, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29767558

RESUMO

Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine A(CSA). In this study, we tested the hypothesis that administration of calcium channel blockers such as verapamil or nifedipine ameliorates renal CSA-induced renal dysfunction. Furthermore, our study investigates the roles of inflammatory, oxidative, and fibrotic pathways in CSA-induced renal dysfunction. Six groups of male rats ( n = 6/group) were used and received one of the following treatments for seven consecutive days: vehicle (Cremophor EL ip), CSA (25 mg·kg-1·day-1 ip), verapamil (2 mg·kg-1·day-1 ip), nifedipine (3 mg·kg-1·day-1 ip), CSA in the presence or absence of either verapamil, or nifedipine. Biochemical and histomorphometric analyses showed that rats treated with CSA exhibited clear signs of nephrotoxicity that included 1) proteinuria and elevations in serum creatinine and blood urea nitrogen, 2) mesangial expansion, 3) increases in glomerular and tubular type IV collagen expression, and 4) increases in the glomerulosclerosis and tubulointerstitial fibrosis indices. Although the single administration of nifedipine or verapamil had no significant effect on renal pathology, or its biochemical and physiological function, the concurrent use of either calcium channel blockers significantly and equipotently ameliorated the biochemical, morphological, and functional derangements caused by CSA. More importantly, we report that the oxidative (reactive oxygen species production, NADPH-oxidase activity, and dual oxidase 1/2 levels), fibrotic (transforming growth factor-ß1 expression), and inflammatory (NF-κB expression) manifestations of renal toxicity induced by CSA were significantly reversed upon administration of nifedipine or verapamil. Together, these results highlight the efficacy of calcium channel-blocking agents in attenuating CSA-induced nephrotoxicity and predisposing biochemical and molecular machineries.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Ciclosporina , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Nifedipino/farmacologia , Verapamil/farmacologia , Animais , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Colágeno Tipo IV/metabolismo , Creatinina/sangue , Oxidases Duais/metabolismo , Fibrose , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Masculino , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Proteinúria/prevenção & controle , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo
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