Abstract
BackgroundBuyang Huanwu Decoction (BHD) is a classical Chinese Medicine formula empirically used for diabetic nephropathy (DN). However, its therapeutic efficacies and the underlying mechanisms remain obscure. In our study, we aim to evaluate the renoprotective effect of BHD on a streptozotocin (STZ)-induced diabetic nephropathy mouse model and explore the potential underlying mechanism in mouse mesangial cells (MCs) treated with high glucose in vitro, followed by screening the active compounds in BHD.MethodsMice were received 50 mg/kg streptozotocin (STZ) or citrate buffer intraperitoneally for 5 consecutive days. BHD was intragastrically administrated for 12 weeks starting from week 4 after the diabetes induction. The quality control and quantitative analysis of BHD were studied by high-performance liquid chromatography (HPLC). Renal function was evaluated by urinary albumin excretion (UAE) using ELISA. The mesangial matrix expansion and renal fibrosis were measured using periodic acid-schiff (PAS) staining and Masson Trichrome staining. Mouse mesangial cells (MCs) were employed to study molecular mechanisms.ResultsWe found that the impaired renal function in diabetic nephropathy was significantly restored by BHD, as indicated by the decreased UAE without affecting the blood glucose level. Consistently, BHD markedly alleviated STZ-induced diabetic glomerulosclerosis and tubulointerstitial injury as shown by PAS staining, accompanied by a reduction of renal inflammation and fibrosis. Mechanistically, BHD inhibited the activation of TGF-β1/Smad3 and NF-κB signaling in diabetic nephropathy while suppressing Arkadia expression and restoring renal Smad7. We further found that calycosin-7-glucoside (CG) was one of the active compounds from BHD, which significantly suppressed high glucose-induced inflammation and fibrosis by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways in mesangial cells.ConclusionBHD could attenuate renal fibrosis and inflammation in STZ-induced diabetic kidneys via inhibiting TGF-β1/Smad3 and NF-κB signaling while suppressing the Arkadia and restoring renal Smad7. CG could be one of the active compounds in BHD to suppress renal inflammation and fibrosis in diabetic nephropathy.
Highlights
Diabetic nephropathy (DN) is the main cause of endstage renal disease (ESRD) with high morbidity and mortality in diabetes mellitus (DM) patients [1]
To the best of our knowledge, it is the first time to report that Buyang Huanwu Decoction (BHD) and its active compound CG could protect against diabetic nephropathy via inhibiting transforming growth factor β1 (TGF-β1)/Smad3/Nuclear factor-κB (NF-κB) signaling
We found that BHD reduced the expressions of pro-inflammatory cytokines (TNF-α and IL-1β) and fibrosis-related proteins, and inhibited the TGF-β1/ Smad3 and NF-κB signaling pathway
Summary
Diabetic nephropathy (DN) is the main cause of endstage renal disease (ESRD) with high morbidity and mortality in diabetes mellitus (DM) patients [1]. In the progression of diabetic nephropathy, renal inflammation and fibrosis consistently appear, eventually leading to renal injury [3]. Multiple signaling pathways participate in the pathological process of renal inflammation and fibrosis during diabetic nephropathy. Among them, transforming growth factor β1 (TGF-β1) mediated Smad signaling is a representative signaling pathway contributing to diabetic nephropathy. Smad knock-out mice or Smad inhibitors attenuate renal fibrosis and inflammation in diabetic mice, suggesting that the TGF-β1/Smad signaling pathway contributes to renal fibrosis and inflammation in diabetic nephropathy [7,8,9]. Suppression of TGF-β1/Smad signaling represents a critical therapeutic approach to reduce renal inflammation and fibrosis in diabetic nephropathy [9, 12, 13]. We aim to evaluate the renoprotective effect of BHD on a streptozotocin (STZ)-induced diabetic nephropathy mouse model and explore the potential underlying mechanism in mouse mesangial cells (MCs) treated with high glucose in vitro, followed by screening the active compounds in BHD
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