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1.
Am J Physiol Cell Physiol ; 326(4): C1272-C1290, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38602847

RESUMO

Sodium-glucose cotransporter, type 2 inhibitors (SGLT2i) are emerging as the gold standard for treatment of type 2 diabetes (T2D) with renal protective benefits independent of glucose lowering. We took a high-level approach to evaluate the effects of the SGLT2i, empagliflozin (EMPA) on renal metabolism and function in a prediabetic model of metabolic syndrome. Male and female 12-wk-old TallyHo (TH) mice, and their closest genetic lean strain (Swiss-Webster, SW) were treated with a high-milk-fat diet (HMFD) plus/minus EMPA (@0.01%) for 12-wk. Kidney weights and glomerular filtration rate were slightly increased by EMPA in the TH mice. Glomerular feature analysis by unsupervised clustering revealed sexually dimorphic clustering, and one unique cluster relating to EMPA. Periodic acid Schiff (PAS) positive areas, reflecting basement membranes and mesangium were slightly reduced by EMPA. Phasor-fluorescent life-time imaging (FLIM) of free-to-protein bound NADH in cortex showed a marginally greater reliance on oxidative phosphorylation with EMPA. Overall, net urine sodium, glucose, and albumin were slightly increased by EMPA. In TH, EMPA reduced the sodium phosphate cotransporter, type 2 (NaPi-2), but increased sodium hydrogen exchanger, type 3 (NHE3). These changes were absent or blunted in SW. EMPA led to changes in urine exosomal microRNA profile including, in females, enhanced levels of miRs 27a-3p, 190a-5p, and 196b-5p. Network analysis revealed "cancer pathways" and "FOXO signaling" as the major regulated pathways. Overall, EMPA treatment to prediabetic mice with limited renal disease resulted in modifications in renal metabolism, structure, and transport, which may preclude and underlie protection against kidney disease with developing T2D.NEW & NOTEWORTHY Renal protection afforded by sodium glucose transporter, type 2 inhibitors (SGLT2i), e.g., empagliflozin (EMPA) involves complex intertwined mechanisms. Using a novel mouse model of obesity with insulin resistance, the TallyHo/Jng (TH) mouse on a high-milk-fat diet (HMFD), we found subtle changes in metabolism including altered regulation of sodium transporters that line the renal tubule. New potential epigenetic determinants of metabolic changes relating to FOXO and cancer signaling pathways were elucidated from an altered urine exosomal microRNA signature.


Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Nefropatias , MicroRNAs , Neoplasias , Estado Pré-Diabético , Inibidores do Transportador 2 de Sódio-Glicose , Masculino , Feminino , Camundongos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estado Pré-Diabético/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Rim , Glucose/farmacologia , MicroRNAs/farmacologia , Sódio
2.
Int Immunopharmacol ; 116: 109785, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36720193

RESUMO

The PI3K/AKT and p53 pathways are key regulators of cancer cell survival and death, respectively. Contrary to their generally accepted roles, several lines of evidence, including ours in medulloblastoma, the most common childhood brain cancer, highlight non-canonical functions for both proteins and show a complex context-dependent dynamic behavior in determining cell fate. Interestingly, p53-mediated cell survival and AKT-mediated cell death can dominate in certain conditions, and these interchangeable physiological functions may potentially be manipulated for better clinical outcomes. This review article presents studies in which p53 and AKT behave contrary to their well-established functions. We discuss the factors and circumstances that may be involved in mediating these changes and the implications of these unique roles of p53 and AKT in devising therapeutic strategies. Lastly, based on our recent finding of Thymosin beta 4-mediated chemosensitivity via an AKT-p53 interaction in medulloblastoma cells, we also discuss the possible implications of Thymosin beta-4 in enhancing drug sensitivity in this deadly childhood disease.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Timosina , Humanos , Criança , Proteínas Proto-Oncogênicas c-akt/metabolismo , Meduloblastoma/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Timosina/genética , Timosina/metabolismo , Neoplasias Cerebelares/tratamento farmacológico
3.
Int J Mol Sci ; 23(10)2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35628485

RESUMO

Sodium-glucose co-transporters (SGLTs) serve to reabsorb glucose in the kidney. Recently, these transporters, mainly SGLT2, have emerged as new therapeutic targets for patients with diabetes and kidney disease; by inhibiting glucose reabsorption, they promote glycosuria, weight loss, and improve glucose tolerance. They have also been linked to cardiac protection and mitigation of liver injury. However, to date, the mechanism(s) by which SGLT2 inhibition promotes systemic improvements is not fully appreciated. Using an obese TallyHo mouse model which recapitulates the human condition of diabetes and nonalcoholic fatty liver disease (NAFLD), we sought to determine how modulation of renal glucose handling impacts liver structure and function. Apart from an attenuation of hyperglycemia, Empagliflozin was found to decrease circulating triglycerides and lipid accumulation in the liver in male TallyHo mice. This correlated with lowered hepatic cholesterol esters. Using in vivo MRI analysis, we further determined that the reduction in hepatic steatosis in male TallyHo mice was associated with an increase in nuchal white fat indicative of "healthy adipose expansion". Notably, this whitening of the adipose came at the expense of brown adipose tissue. Collectively, these data indicate that the modulation of renal glucose handling has systemic effects and may be useful as a treatment option for NAFLD and steatohepatitis.


Assuntos
Tecido Adiposo Branco , Diabetes Mellitus , Hepatopatia Gordurosa não Alcoólica , Inibidores do Transportador 2 de Sódio-Glicose , Tecido Adiposo Marrom , Tecido Adiposo Branco/crescimento & desenvolvimento , Animais , Compostos Benzidrílicos/farmacologia , Glucose/metabolismo , Glucosídeos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/complicações , Obesidade/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
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