Asiatic acid attenuates tubular injury in diabetic kidney disease by regulating mitochondrial dynamics via the Nrf-2 pathway.

BACKGROUND: Mitochondrial dynamics plays a crucial role in tubular injury in diabetic kidney disease (DKD). Asiatic acid (AA) has demonstrated renal protective effects in DKD; however, its therapeutic effect on tubular injury in DKD remains unclear. PURPOSE: This study aimed to verify the effects of AA on tubular injury in DKD and underlying mechanisms. STUDY DESIGN: In the present study, the effects of AA on tubular injury were assessed in rats with streptozotocin-induced diabetes and advanced glycation end products (AGEs)-stimulated HK-2 cells models. METHODS: After oral administration with or without AA for ten weeks, body weight and levels of fast blood glucose, serum creatinine (sCr), blood urea nitrogen (BUN), urinary albumin, and kidney injury molecule-1 (KIM-1) were detected. Histological analysis was performed to evaluate the renal function of rats. Moreover, the expression of proteins associated with the Nrf-2 pathway and mitochondrial dynamics was analyzed. AGEs-stimulated HK-2 cells were examined to evaluate the tubular protection and the mechanism of AA in vitro. RESULTS: AA remarkably decreased albumin levels, KIM-1 levels in urine, and serum Cr, and BUN levels. In addition, AA prevented tubular injury and mitochondrial injury by regulating the Nrf-2 pathway and mitochondrial dynamics. Furthermore, the effects of AA on mitochondrial dynamics and tubular protection were eliminated after treatment with ML385 (Nrf2 inhibitor). CONCLUSION: These findings suggested that AA might be developed as a potential candidate for the treatment of tubular injury in DKD, and its effects are potentially mediated via the regulation of the Nrf-2 pathway and mitochondrial dynamics.

New triterpenoids from the Cyclocarya paliurus (Batalin) Iljinskaja and their anti-fibrotic activity.

Cyclocarya paliurus, a Chinese herbal medicine and new food resource, contains a triterpenic-acid-rich extract that demonstrated ameliorative effect on diabetic nephropathy (DN). A more in-depth discovery of functional components led to the isolation of seven new triterpenoids including two pentacyclic triterpenes, 1α,2α,3ß,23-tetrahydroxyolean-12-en-28-oic acid and 2α,3ß,22α-tirhydroxyurs-12-en-28-oic acid 28-O-ß-D-glucopyranoside, and five tetracyclic triterpenoid glycosides (cypaliurusides N-R), together with twelve known compounds from the leaves of C. paliurus. Their structures were determined using a comprehensive analysis of chemical and spectroscopic data. Partial compounds were assessed for anti-fibrotic activities in high-glucose and TGF-ß1 induced HK-2 cells. Compound 16 remarkably decreased the level of fibronectin with an inhibition rate of 37.1%. Furthermore, 16 effectively alleviated the epithelial-mesenchymal transformation (EMT) process by upregulating E-cadherin expression and downregulating α-SMA expression, and it significantly decreased the level of the transcriptional inhibitors (Snail and Twist) of E-cadherin. The discovery of anti-fibrotic compounds from C. paliurus provides the potential utilization and functional candidates for the DN prevention.

Cyclocarya paliurus triterpenoids attenuate glomerular endothelial injury in the diabetic rats via ROCK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Cyclocarya paliurus (Batal.) Iljinskaja. (C. paliurus) is a distinctive traditional Chinese herb, with remarkable hypoglycemic capacity. Emerging evidence suggested that glomerular endothelial injury is a crucial pathological process of diabetic kidney disease (DKD). Our previous research found that C. paliurus triterpenoids fraction (CPT) has ameliorative effects on DKD. However, whether C. paliurus could counteract the glomerular endothelial injury of DKD is still undefined. AIM OF THE STUDY: We aimed to investigate the effects of CPT on glomerular endothelial function and explore its underlying mechanisms with in vivo and in vitro experiments. MATERIALS AND METHODS: The effects and possible mechanisms of CPT on glomerular endothelial injury in streptozotocin (STZ)-induced diabetic rats and H2O2-challenged primary rat glomerular endothelial cells were successively investigated. RESULTS: In vivo, we found that CPT treatment obviously decreased the levels of blood glucose, microalbumin, BUN and mesangial expansion. Additionally, CPT could ameliorate renal endothelium function by reducing the content of VCAM-1 and ICAM-1, and blocking the loss of glycocalyx. In vitro, CPT could also alleviate H2O2-induced endothelial injury. Mechanistically, CPT remarkably increased the phosphorylation levels of Akt and eNOS, decreased the expression of ROCK and Arg2in vivo and in vitro. Noticeably, the favorable effects mediated by CPT were abolished following ROCK overexpression with plasmid transfection. CONCLUSION: These findings suggested that CPT could be sufficient to protect against glomerular endothelial injury in DKD through regulating ROCK pathway.