Salvianolic Acid A Protects Against Diabetic Nephropathy through Ameliorating Glomerular Endothelial Dysfunction via Inhibiting AGE-RAGE Signaling

Abstract

Background/Aims: Glomerular endothelium dysfunction leads to the progression of renal architectonic and functional abnormalities in early-stage diabetic nephropathy (DN). Advanced glycation end products (AGEs) and receptor for AGEs (RAGE) are proved to play important roles in diabetic nephropathy. This study investigated the role of Salvianolic acid A (SalA) on early-stage DN and its possible underlying mechanism. Methods: In vitro AGEs formation and breaking rate were measured to illustrate the effect of SalA on AGEs. Type 2 diabetic nephropathy rats were induced by high-fat diet and low-dose streptozocin (STZ). After eight-week treatment with SalA 1 mg/kg/day, 24h-urine protein, creatinine clearance was tested and renal structural injury was assessed by PAS and PASM staining. Primary glomerular endothelial cell permeability was evaluated after exposed to AGEs. AGEs-induced RhoA/ROCK and subsequently activated disarrange of cytoskeleton were assessed by western blot and immunofluorescence. Results: Biochemical assay and histological examination demonstrated that SalA markedly reduced endothelium loss and glomerular hyperfiltration, suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced urinary albumin and ameliorated renal function. Further investigation suggested that SalA exerted its renoprotective effects through inhibiting AGE-RAGE signaling. It not only inhibited formation of AGEs and increased its breaking in vitro, but also reduced AGEs accumulation in vivo and downregulated RAGE expression. SalA restored glomerular endothelial permeability through suppressing AGEs-induced rearrangement of actin cytoskeleton via AGE-RAGE-RhoA/ ROCK pathway. Moreover, SalA attenuated oxidative stress induced by AGEs, subsequently alleviated inflammation and restored the disturbed autophagy in glomerular endothelial cell and diabetic rats via AGE-RAGE-Nox4 axis. Conclusion: Our study indicated that SalA restored glomerular endothelial function and alleviated renal structural deterioration through inhibiting AGE-RAGE, thus effectively ameliorated early-stage diabetic nephropathy. SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.

Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products

“…In addition, some commercial drugs approved by FDA were reported to show serious side effects, which severely impeded their clinical use, hinting new drugs and strategies are urgently needed [14][15][16]. In this review, we highlight a number of natural products that could target the above-mentioned mediators as exemplified by 25-O-methylalisol F [17], poricoic acid ZA [18] and salvianolic acid A [19], which might provide novel therapeutic strategy for the treatment of renal diseases.…”

Corin plays a protective role via upregulating MAPK and downregulating eNOS in diabetic nephropathy endothelial dysfunction

“…15,20 Endothelial dysfunction leads to renal structural and functional abnormalities in DN. 21 We showed that a lack of Corin in HK-2 cells could attenuate endothelial migration of EA.hy926 cells through paracrine crosstalk that is likely mediated by ANP. Our previous studies on DCM revealed that Corin from cardiomyocytes affects endothelial cells in a similar fashion.…”

Downregulation of miR-31 in Diabetic Nephropathy and its Relationship with Inflammation

“…Although a lot of research has been done on the search of novel treatments for established DN [17][18][19], the development of tools for the early detection and prognosis of DN is needed in order to identify patients at risk and carry out interventional strategies to prevent the onset of DN. Several miRNAs have been related to the pathological mechanisms of DN [20]; for example, miR-192, which is specifically expressed in the kidney, is downregulated in patients with established DN, and has been related to increased fibrosis and reduced eGFR [21].…”