A study of the effects of SGLT-2 inhibitors on diabetic cardiomyopathy through miR-30d/KLF9/VEGFA pathway
EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES
Authors: Zhang, W-Y; Wang, J.; Li, A-Z
Abstract
OBJECTIVE: The aim of this study was to observe the protective effects of SGLT-2 inhibitors on diabetic cardiomyopathy. MATERIALS AND METHODS: After constructing a diabetic rat model, the effects of SGLT-2 (Sodium-Glucose Cotransporter-2) inhibitors and miR-30d on cardiac function in rats were investigated by cardiac echocardiography, hematoxylin-eosin (HE) staining. and immunohistochemical methods. At the same time, changes in autophagy levels in rats were detected by Western blot (WB) experiments. RESULTS: SGLT-2 inhibitors improved the cardiac function of diabetic rats, and alleviated the pathological damage of myocardial tissue. Besides. knocking down miR-30d prevented the decrease of cardiac function in diabetic rats. Moreover, miR-30d could regulate the expression of the KLF9/VEGFA pathway and inhibit autophagy in rats. CONCLUSIONS: SGLT-2 inhibitors can regulate the autophagy level in diabetic rats through the miR-30d/KLF9/VEGFA pathway. thereby improving cardiac function.
VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy
JOURNAL OF CLINICAL MEDICINE
Authors: Lavoz, Carolina; Rodrigues-Diez, Raul R.; Plaza, Anita; Carpio, Daniel; Egido, Jesus; Ruiz-Ortega, Marta; Mezzano, Sergio
Abstract
The absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the effects of its blockade in experimental models of DN is still controversial. Here, we test the effects of a therapeutic anti-VEGFR2 treatment, using a VEGFR2 kinase inhibitor, on the progression of renal damage in the BTBR ob/ob (leptin deficiency mutation) mice. This experimental diabetic model develops histological characteristics mimicking the key features of advanced human DN. A VEGFR2 pathway-activation blockade using the VEGFR2 kinase inhibitor SU5416, starting after kidney disease development, improves renal function, glomerular damage (mesangial matrix expansion and basement membrane thickening), tubulointerstitial inflammation and tubular atrophy, compared to untreated diabetic mice. The downstream mechanisms involved in these beneficial effects of VEGFR2 blockade include gene expression restoration of podocyte markers and downregulation of renal injury biomarkers and pro-inflammatory mediators. Several ligands can activate VEGFR2, including the canonical ligands VEGFs and GREMLIN. Activation of a GREMLIN/VEGFR2 pathway, but not other ligands, is correlated with renal damage progression in BTBR ob/ob diabetic mice. RNA sequencing analysis of GREMLIN-regulated genes confirm the modulation of proinflammatory genes and related-molecular pathways. Overall, these data show that a GREMLIN/VEGFR2 pathway activation is involved in diabetic kidney disease and could potentially be a novel therapeutic target in this clinical condition.