SGLT2 inhibitor empagliflozin ameliorates tubulointerstitial fibrosis in DKD by downregulating renal tubular PKM2

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 2, 2025

Background and Objective Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to prevent the progression of diabetic kidney disease (DKD). However, their impact on renal fibrosis remains largely uninvestigated. This study aimed explore effect SGLT2 inhibitor empagliflozin in DKD patients models, molecular mechanisms involved. Methods Kidney samples models were used this study. mouse included STZ-treated CD-1 mice HFD-fed C57BL/6 all treated with for 6 12 weeks. pathological changes analysed fibrotic factors detected. HK-2 cells normal glucose (NG), high (HG), or HG empagliflozin. RNA sequencing was employed identify differentially expressed genes. Epithelial–mesenchymal transition (EMT) markers Binding transcription factor target gene determined using a dual-luciferase reporter assay. Results Empagliflozin significantly ameliorated models. evidenced by tubulointerstitial reduction observed through PAS Masson staining, along downregulation. subsequent in vitro vivo validation identified PKM2 as most upregulated glycolytic enzyme downregulated alleviated EMT fibrosis. Importantly, improves downregulating PKM2. The downregulation achieved inhibiting binding estrogen-related receptor α at promoter. Conclusions ameliorates via DKD.

Язык: Английский

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A systematic review and meta‐analysis of the effects of diabetes on human and murine epididymis

Andrology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Diabetes mellitus has increased significantly over the past decades. This disease affects reproductive competence of diabetic men by disrupting spermatogenesis, fertility potential, penile erection, and ejaculation. However, hyperglycemic conditions' effects on epididymis remain elusive despite its importance for sperm maturation. We aimed to determine diabetes epididymis, using qualitative (systematic review) quantitative (meta-analysis) approaches, address question: Can disrupt epididymal structure function? performed an extensive literature search identifying 66 eligible studies through PubMed, Web Science, Embase databases. Outcomes extracted from included alterations in cell metabolism morphology under conditions. Pre-clinical published murine were evaluated a meta-analytical approach, whereas clinical investigations humans analyzed qualitatively (PROSPERO number is CRD42020208658). Type 1 patients presented post-ejaculatory hypotonia/atonia, type 2 exhibited perturbation advanced glycation end-product axis. In murine, high glucose levels disturb cells, androgenic profile, expression hormone receptors within organ. The low activity antioxidant enzymes promoted elevation oxidative metabolite levels, creating pro-oxidant microenvironment toxic spermatozoa. All these deleterious mechanisms trigger molecular biochemical responses contributing deterioration function. Our data indicated that may affect function hormonal imbalance, disturbance, stress generation. These alter luminal epithelial function, impairing organ functionality with consequences review also highlighted several points need investigation further associating fill knowledge gaps better.

Язык: Английский

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SGLT2 inhibitor empagliflozin ameliorates tubulointerstitial fibrosis in DKD by downregulating renal tubular PKM2

Cellular and Molecular Life Sciences, Год журнала: 2025, Номер 82(1)

Опубликована: Апрель 16, 2025

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to prevent the progression of diabetic kidney disease (DKD). However, their impact on renal fibrosis remains largely uninvestigated. This study aimed explore effect SGLT2 inhibitor empagliflozin in DKD patients and models, molecular mechanisms involved. Kidney samples models were used this study. mouse included STZ-treated CD-1 mice HFD-fed C57BL/6 all treated with for 6 12 weeks. pathological changes analysed fibrotic factors detected. HK-2 cells normal glucose (NG), high (HG), or HG empagliflozin. RNA sequencing was employed identify differentially expressed genes. Epithelial-mesenchymal transition (EMT) markers Binding transcription factor target gene determined using a dual-luciferase reporter assay. Empagliflozin significantly ameliorated models. evidenced by tubulointerstitial reduction observed through PAS Masson staining, along downregulation. subsequent vitro vivo validation identified PKM2 as most upregulated glycolytic enzyme downregulated alleviated EMT fibrosis. Importantly, improves downregulating PKM2. The downregulation achieved inhibiting binding estrogen-related receptor α at promoter. ameliorates via DKD.

Язык: Английский

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NRF2 Deficiency Attenuates Diabetic Kidney Disease in Db/Db Mice via Down-Regulation of Angiotensinogen, SGLT2, CD36, and FABP4 Expression and Lipid Accumulation in Renal Proximal Tubular Cells

Antioxidants, Год журнала: 2023, Номер 12(9), С. 1715 - 1715

Опубликована: Сен. 4, 2023

The role(s) of nuclear factor erythroid 2-related 2 (NRF2) in diabetic kidney disease (DKD) is/are controversial. We hypothesized that Nrf2 deficiency type diabetes (T2D) db/db mice (db/dbNrf2 knockout (KO)) attenuates DKD progression through the down-regulation angiotensinogen (AGT), sodium-glucose cotransporter-2 (SGLT2), scavenger receptor CD36, and fatty -acid-binding protein 4 (FABP4), lipid accumulation renal proximal tubular cells (RPTCs). Db/dbNrf2 KO were studied at 16 weeks age. Human RPTCs (HK2) with NRF2 via CRISPR-Cas9 genome editing kidneys from patients or without T2D examined. Compared mice, db/dbNrf2 had lower systolic blood pressure, fasting glucose, hypertrophy, glomerular filtration rate, urinary albumin/creatinine ratio, droplet accumulation, decreased expression AGT, SGLT2, FABP4 RPTCs. Male female similar results. attenuated stimulatory effect activator, oltipraz, on CD36 high-glucose/free acid (FFA)-stimulated HK2. Kidneys exhibited markedly higher levels than non-diabetic patients. These data suggest exacerbates stimulation T2D.

Язык: Английский

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The emerging insight into E3 ligases as the potential therapeutic target for diabetic kidney disease

Life Sciences, Год журнала: 2023, Номер 321, С. 121643 - 121643

Опубликована: Март 28, 2023

Язык: Английский

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