Suxia Yang

Naringin ameliorates diabetic nephropathy by inhibiting NADPH oxidase 4

Abstract Naringin, a naturally flavanone glycoside, has been previously demonstrated to alleviate diabetic kidney disease by inhibiting oxidative stress and inflammatory reaction. However, the underlying mechanism of naringin in diabetic nephropathy (DN) has not been fully elucidated. Here, the beneficial effect of naringin on DN in streptozotocin (STZ)‐induced DN rats and high glucose (HG)‐induced podocytes and its underlying mechanism were elaborated. The result revealed that naringin alleviated STZ‐induced renal dysfunction and injury in DN rats, relieved STZ‐induced oxidative stress in vivo and inhibited HG‐induced apoptosis and reactive oxygen species level i20n vitro. More importantly, naringin inhibited NOX4 expression at mRNA and protein levels in STZ‐induced DN rats and HG‐induced podocytes. Loss of function indicated that NADPH oxidases 4 (NOX4) down‐regulation suppressed apoptosis and reactive oxygen species level in HG‐treated podocytes. Take together, this study demonstrated that naringin ameliorates diabetic nephropathy by inhibiting NOX4, contributing to a better understanding of the progression of DN.

Protocatechuic acid ameliorates high glucose-induced extracellular matrix accumulation in diabetic nephropathy

Protocatechuic acid (PCA), a phenolic compound of anthocyanins, was reported to possess various pharmacologic properties, including anti-oxidant, anti-inflammatory, anti-apoptosis, anti-diabetic and anti-tumor activities. However, the role of PCA in diabetic nephropathy remains elusive. The present study was conducted to evaluate the effects of PCA on extracellular matrix (ECM) accumulation in high glucose (HG)-induced human mesangial cells (MCs) and explore the possible mechanism. Our results demonstrated that PCA obviously inhibited HG-induced proliferation of MCs in a dose-dependent manner. In addition, PCA effectively reduced the protein expression levels of type IV collagen, laminin and fibronectin induced by HG, as well as decreased the levels of ROS and MDA in HG-stimulated MCs. Mechanistic studies showed that PCA efficiently down-regulated the phosphorylation level of p38 MAPK in HG-stimulated MCs. Taken together, our present study demonstrated that PCA protects MCs against HG damage might via inhibition of the p38 MAPK signaling pathway. Thus, PCA might be a beneficial agent for the prevention and treatment of diabetic nephropathy.

SOCS2 overexpression alleviates diabetic nephropathy in rats by inhibiting the TLR4/NF-κB pathway

Suppressor of cytokine signaling 2 (SOCS2) was reported to be involved in the development of Diabetic Nephropathy (DN). However, its underlying mechanism remains undefined. Western blot was carried out to determine the expressions of SOCS2, Toll-like receptors 4 (TLR4) and nuclear factor kappa B (NF-κB) pathway-related proteins in DN patients, streptozotocin (STZ)-induced DN rats and high glucose (HG)-stimulated podocytes. The effects of SOCS2 overexpression on renal injury, the inflammatory cytokines production, renal pathological changes, apoptosis and the TLR4/NF-κB pathway in DN rats or HG-stimulated podocytes were investigated. TLR4 antagonist TAK-242 and NF-κB inhibitor PDTC were used to confirm the functional mechanism of SOCS2 overexpression in HG-stimulated podocytes. SOCS2 was down-regulated, while TLR4 and NF-κB were up-regulated in renal tissues of DN patients and DN rats. Ad-SOCS2 infection alleviated STZ-induced renal injury and pathological changes and inhibited STZ-induced IL-6, IL-1β and MCP-1 generation and activation of the TLR4/NF-κB pathway in DN rats. SOCS2 overexpression attenuated apoptosis, suppressed the inflammatory cytokines expression, and inactivated the TLR4/NF-κB pathway in HG-stimulated podocytes. Suppression of the TLR4/NF-κB pathway enhanced the inhibitory effect of SOCS2 overexpression on apoptosis and inflammatory cytokines expressions in HG-stimulated podocytes. SOCS2 overexpression alleviated the development of DN by inhibiting the TLR4/NF-κB pathway, contributing to developing new therapeutic strategies against DN.

Silencing of TRB3 Ameliorates Diabetic Tubule Interstitial Nephropathy via PI3K/AKT Signaling in Rats

Background Nephropathy, a chronic progressive kidney disease often characterized by glomeruli scarring and sclerosis, is a major complication of diabetes mellitus. Development of nephropathologic lesions has been shown to be associated with suppressed AKT phosphorylation and elevated level of apoptosis. Moreover, it has been established that the TRB3 gene is capable of inhibiting AKT phosphorylation and promoting apoptosis. Material/Methods In this study, we injected TRB3 siRNA into Wistar rats with type 1 diabetes, and monitored development of nephropathy in the rats. Urinary albumin excretion and serum creatinine were used as primary indicators, and nephritic histology was also examined. We also measured the serum level of pro-inflammatory cytokines collagen expression, and phosphorylation of PI3K and AKT proteins in the kidneys. Results By silencing the TRB3 gene with siRNA, diabetic-induced nephropathy symptoms were alleviated, such as increased serum creatinine level and urinary albumin secretion. Additionally, histological examination showed lower levels of nephropathic lesions, and samples of the kidneys showed less accumulation of collagen proteins. Levels of serum cytokines, including TNF-α, IL-1β, and IL-6, were also lowered, whereas phosphorylation levels of PI3K and AKT were increased. In summary, TRB3 silencing in diabetic rats had a significant ameliorative effect on their nephropathy. Conclusions Silencing of TRB3 has a significant ameliorative effect on diabetic nephropathy in rats.

Knockdown of Angiopoietin-Like Protein 2 Ameliorates Diabetic Nephropathy by Inhibiting TLR4

Background/Aims: Angiopoietin-like protein 2 (ANGPTL2) was reported to be implicated in the pathogenesis of inflammatory disease. Its role in diabetic nephropathy (DN) remained illdefined. Methods: qRT-PCR and western blot analysis were performed to detect the expressions of ANGPTL2 or TLR4 in streptozotocin (STZ)-induced DN rats and HG-stimulated podocytes. The renal injury index including 24-h proteinuria, blood glucose level, serum creatinine and blood urea nitrogen were measured in DN rats using corresponding commercial kits. The effect of ANGPTL2 knockdown on the secretion or expression of inflammatory cytokines was detected by ELISA or qRT-PCR analysis. The effect of ANGPTL2 knockdown on extracellular matrix (ECM) accumulation was determined by testing TGF-β1, Collagen-IV, fibronectin (FN) and PTEN expression via western blot. Results: ANGPTL2 and TLR4 were both highly expressed in DN rats compared with control group. ANGPTL2 knockdown alleviated renal injury in STZ-induced DN rat model. ANGPTL2 knockdown also suppressed inflammatory cytokines (IL-6, TNF-α, MCP-1, IL-1β) expression and ECM accumulation (TGF-β1, Collagen-IV, FN, PTEN) in HG-induced podocytes. Moreover, ANGPTL2 knockdown led to a significant decrease of TLR4 expression in both DN rat and cell model. Furthermore, TAK-242 treatment exacerbated the inhibitory effect of ANGPTL2 knockdown on inflammatory cytokines expression and ECM accumulation in HG-induced podocytes. Conclusion: ANGPTL2 knockdown ameliorates DN by inhibiting TLR4 expression, an observation contributing to a better understanding of DN pathogenesis.

Ginkgetin aglycone ameliorates LPS-induced acute kidney injury by activating SIRT1 via inhibiting the NF-κB signaling pathway

BackgroundGinkgetin aglycone (GA), a novel Ginkgo biloba extract (GBE) by acid hydrolysis and recrystallization, is characterized by higher liposolubility and antioxidation than classical GBEs. There is no study depicting the functional role of GA in acute kidney injury (AKI). Here, we firstly reported the protective effect of GA on lipopolysaccharide (LPS)-induced AKI and its underlying mechanism.MethodsELISA analysis was applied to measure plasma level of TNF-α and IL-6, and NF-κB activity in kidney homogenate. Renal function analysis was performed by detecting serum concentration of Kim-1 and urine level of BUN. Cell apoptosis in kidney tissues was detected by TUNEL assay and caspase-3 activity assay. qRT-PCR was conducted to determine mRNA expression of TNF-α, IL-6 and IκBα. Western blot was carried out to confirm expression of p-IκBα, SIRT1, and iNOS.ResultsGA administration protected mice from LPS-induced AKI by attenuating inflammatory response, renal injury, as well as tubular apoptosis both in vivo. GA suppressed inflammatory response induced by LPS in HK-2 cells. Moreover, GA upregulated SIRT1 expression and blocked the NF-κB signaling pathway in LPS-induced AKT in vivo and vitro. Furthermore, suppression of SIRT1 abated the inhibitory effect of GA on LPS-induced inflammatory response and renal injury.ConclusionsGA prevented LPS-induced AKI by activating SIRT1 via inhibiting the NF-κB signaling pathway, providing new insights into the function and molecular mechanism of GA in AKI. Therefore, GA may be a promising therapeutic agent for the treatment of septic AKI.

Effects of Renal Denervation on Cardiac Structural and Functional Abnormalities in Patients with Resistant Hypertension or Diastolic Dysfunction

The aim of the present study is to systematically evaluate the impact of RDN on cardiac structure and function in patients with resistant hypertension (RH) or diastolic dysfunction. We retrieved Pubmed, Embase and Cocharane Library databases, from inception to April 1st, 2016. Studies reporting left ventricular mass (LVMI) or left ventricular (LV) diastolic function (reflected by the ratio of mitral inflow velocity to annular relaxation velocity [E/e’]) responses to RDN were included. Two randomized controlled trials (RCTs), 3 controlled studies and 11 uncontrolled studies were finally identified. In observational studies, there was a reduction in LVMI, E/e’ and N-terminal pro B-type natriuretic peptide (BNP) at 6 months, compared with pre-RDN values. LV ejection fraction (LVEF) elevated at 6 months following RDN. In RCTs, however, no significant change in LVMI, E/e’, BNP, left atrial volume index or LVEF was observed at 12 months, compared with pharmaceutical therapy. In summary, both LV hypertrophy and cardiac function improved at 6 months after RDN. Nonetheless, current evidence failed to show that RDN was superior to intensive (optimal) drug therapy in improving cardiac remodeling and function.

Interleukin-18: A Predictive Marker of Major Adverse Cardiovascular Events in Hemodialysis Patients

A prospective observational study was conducted to evaluate the predictive value of interleukin-18 (IL-18) for major adverse cardiovascular events (MACEs) in hemodialysis patients. A total of 85 participants (45 hemodialysis patients and 40 healthy volunteers) with a mean age of 56.3 years were enrolled in this study. Demographic and clinical data were collected. MACE was used as the primary endpoint. Results showed that the hemodialysis patients had higher levels of IL-18 (701.6 ± 88.52 versus 152.0 ± 55.31 pg/mL, P < 0.01) and a high rate of MACE (15.6% versus 2.5%, P < 0.01) compared with healthy controls. Multiple linear regression analysis showed that the serum creatinine and left ventricular ejection fraction were significantly effective factors influencing IL-18 (P < 0.01). Receiver-operating characteristic curve analysis showed that IL-18 levels were better predictors for MACE. The area under the curve of IL-18 was 0.81 (0.70-0.92) (P = 0.004). IL-18 levels provided 87.5% sensitivity and 26% specificity with a threshold value of 534.5 pg/mL. Our findings indicated that hemodialysis patients with high levels of IL-18 had a high incidence rate of MACE. IL-18 is a good predictive marker of MACE in hemodialysis patients.

Knockdown of NLRC5 inhibits renal fibroblast activation via modulating TGF-β1/Smad signaling pathway

&NA; NLRC5, the largest member of the Nucleotide‐binding domain and leucine‐rich repeat (NLR) protein family, is recently proven to be a critical modulator in fibrogenesis. However, the role of NLRC5 in renal fibrosis remains unknown. In the present study, we investigated the effects of NLRC5 on transforming growth factor &bgr;1 (TGF‐&bgr;1)‐stimulated rat renal fibroblasts in vitro. Our results showed that the expression of NLRC5 was also obviously upregulated in renal fibrosis tissues and TGF‐&bgr;1‐treated NRK‐49F cells. Knockdown of NLRC5 inhibited the proliferation of NRK‐49F cells induced by TGF‐&bgr;1, as well as suppressed the accumulation of extracellular matrix (ECM) in NRK‐49F cells induced by TGF‐&bgr;1. Furthermore, knockdown of NLRC5 inhibited the expression of phosphorylated Smad3 in TGF‐&bgr;1‐treated NRK‐49F cells. In conclusion, our results show that knockdown of NLRC5 inhibits renal fibroblast activation via modulating TGF‐&bgr;1/Smad signaling pathway. Therefore, NLRC5 may act as a key mediator in renal fibroblast activation and fibrogenesis.

CTRP6 inhibits cell proliferation and ECM expression in rat mesangial cells cultured under TGF-β1

C1q/tumor necrosis factor-related protein 6 (CTRP6), a member of CTRPs family, was involved in fibrosis. However, the biological function of CTRP6 in renal fibrosis remains elusive. This study aimed to examine the role of CTRP6 in renal fibrosis and explore the possible mechanism. Our results demonstrated that the expression of CTRP6 was significantly downregulated in renal fibrotic tissues and TGF-β1-treated NRK-49F cells. In addition, overexpression of CTRP6 inhibited the proliferation, migration, and ECM expression in TGF-β1-treated NRK-49F cells. Furthermore, overexpression of CTRP6 attenuated TGF-β-induced phosphorylation of ERK1/2 in NRK-49F cells. The ERK1/2 inhibitor U0126 enhanced the inhibitory effects of CTRP6 overexpression on cell proliferation, migration and ECM expression in TGF-β1-stimulated NRK-49F cells. In conclusion, we have demonstrated that CTRP6 suppressed ECM expression in renal fibroblasts induced by TGF-β1 through the ERK signaling pathway. Therefore, CTRP6 may be a potential therapeutic target for the treatment of renal fibrosis.