The Comparation of Renal Anti‐Senescence Effects and Blood Metabolites between Dapagliflozin and Metformin in Non‐Diabetes Environment
Lu Zeng,
Lei Chen,
Fanfan Gao
et al.
Abstract:Delaying kidney senescence process will benefit renal physiologic conditions, and prompt the kidney recovering from different pathological states. The renal anti‐senescence effects of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) and metformin have been proven in diabetic settings, but the roles of each one and combination of two drugs in natural kidney aging process remain undefined and deserve further research. Senescence‐accelerated mouse prone 8 (SAMP8) were orally administered dapagliflozin, metformi… Show more
“…The area sizes of different parts of glomeruli (the detailed shown in Figure S2) 8 were also roughly measured; SAMP8 mice had decreased relative capillary bulb area and increased renal vesicles area, indicating that with the kidney ageing progresses, the glomerular blood perfusion may reduce and leads to atrophy of glomeruli (Table S1).…”
Senescent kidney can lead to the maladaptive repairment and predispose age‐related kidney diseases. Here, we explore the renal anti‐senescence effect of a known kind of drug, sodium‐dependent glucose transporters 2 inhibitor (SGLT2i). After 4 months intragastrically administration with dapagliflozin on senescence‐accelerated mouse prone 8 (SAMP8) strain mice, the physiologically effects (lowering urine protein, enhancing glomerular blood perfusion, inhibiting expression of senescence‐related biomarkers) and structural changes (improving kidney atrophy, alleviating fibrosis, decreasing glomerular mesangial proliferation) indicate the potential value of delaying kidney senescence of SGLT2i. Senescent human proximal tubular epithelial (HK‐2) cells induced by H2O2 also exhibit lower senescent markers after dapagliflozin treatment. Further mechanism exploration suggests LTBP2 have the great possibility to be the target for SGLT2i to exert its renal anti‐senescence role. Dapagliflozin down‐regulate the LTBP2 expression in kidney tissues and HK‐2 cells with senescent phenotypes. Immunofluorescence staining show SGLT2 and LTBP2 exist colocalization, and protein‐docking analysis implies there is salt‐bridge formation between them; these all indicate the possibility of weak‐interaction between the two proteins. Apart from reducing LTBP2 expression in intracellular area induced by H2O2, dapagliflozin also decrease the concentration of LTBP2 in cell culture medium. Together, these results reveal dapagliflozin can delay natural kidney senescence in non‐diabetes environment; the mechanism may be through regulating the role of LTBP2.
“…The area sizes of different parts of glomeruli (the detailed shown in Figure S2) 8 were also roughly measured; SAMP8 mice had decreased relative capillary bulb area and increased renal vesicles area, indicating that with the kidney ageing progresses, the glomerular blood perfusion may reduce and leads to atrophy of glomeruli (Table S1).…”
Senescent kidney can lead to the maladaptive repairment and predispose age‐related kidney diseases. Here, we explore the renal anti‐senescence effect of a known kind of drug, sodium‐dependent glucose transporters 2 inhibitor (SGLT2i). After 4 months intragastrically administration with dapagliflozin on senescence‐accelerated mouse prone 8 (SAMP8) strain mice, the physiologically effects (lowering urine protein, enhancing glomerular blood perfusion, inhibiting expression of senescence‐related biomarkers) and structural changes (improving kidney atrophy, alleviating fibrosis, decreasing glomerular mesangial proliferation) indicate the potential value of delaying kidney senescence of SGLT2i. Senescent human proximal tubular epithelial (HK‐2) cells induced by H2O2 also exhibit lower senescent markers after dapagliflozin treatment. Further mechanism exploration suggests LTBP2 have the great possibility to be the target for SGLT2i to exert its renal anti‐senescence role. Dapagliflozin down‐regulate the LTBP2 expression in kidney tissues and HK‐2 cells with senescent phenotypes. Immunofluorescence staining show SGLT2 and LTBP2 exist colocalization, and protein‐docking analysis implies there is salt‐bridge formation between them; these all indicate the possibility of weak‐interaction between the two proteins. Apart from reducing LTBP2 expression in intracellular area induced by H2O2, dapagliflozin also decrease the concentration of LTBP2 in cell culture medium. Together, these results reveal dapagliflozin can delay natural kidney senescence in non‐diabetes environment; the mechanism may be through regulating the role of LTBP2.
Given the rapid aging of the population, age-related diseases have become an excessive burden on global health care. The kidney, a crucial metabolic organ, ages relatively quickly. While the aging process itself does not directly cause kidney damage, the physiological changes that accompany it can impair the kidney's capacity for selfrepair. This makes aging kidneys more susceptible to diseases, including increased risks of chronic kidney disease and end-stage renal disease. Therefore, delaying the progression of renal aging and preserving the youthful vitality of the kidney are crucial for preventing kidney diseases. However, effective strategies against renal aging are still lacking due to the underlying mechanisms of renal aging, which have not been fully elucidated. Accumulating evidence suggests that metformin has beneficial effects in mitigating renal aging. Metformin has shown promising anti-aging results in animal models but has not been tested for this purpose yet in clinical trials. These findings indicate the potential of metformin as an anti-renal aging drug. In this review, we primarily discuss the characteristics and mechanisms of kidney aging and the potential effects of metformin against renal aging.
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