curcumin and Ureteral-Obstruction

In this study, we explored the role and mechanism of repulsive guidance molecule B (RGMb, also known as Dragon) in the protective effects of curcumin against renal fibrosis and verified Dragon's effect on renal tubular epithelial cell apoptosis and cell programmability. Unilateral ureteral obstruction (UUO) was surgically induced in rats to establish a model of renal interstitial fibrosis (RIF). The rats were then treated with curcumin. Curcumin prominently decreased the serum creatinine (SCr) and blood urea nitrogen (BUN) levels, and also improved the tubular injury in the UUO-induced rats. Curcumin significantly downregulated the TGF-β1, P-Smad2/3, cleaved caspase-3, cleaved caspase-8 and Dragon levels. Dragon knockdown also markedly reduced the TGF-β1, P-Smad2/3, Smad2/3, cleaved caspase-3, cleaved caspase-8, fibronectin, collagen I, collagen IV, vimentin, and α-SMA expression levels. Conversely, Dragon overexpression caused higher expression levels of these proteins, and curcumin reversed this effect. Furthermore, Dragon knockdown increased the E-cadherin levels, whereas Dragon overexpression decreased these levels. Overexpressing Dragon significantly decreased the cell viability, and curcumin reversed this effect. In conclusion, curcumin acted on Dragon and attenuated RIF in UUO rat models. Curcumin downregulated the TGF-β1/Smad signaling pathway and inhibited Dragon and fibrogenic molecules in both rats and HK-2 cells.

Topics: Animals; Blood Urea Nitrogen; Caspase 3; Creatinine; Curcumin; Fibrosis; GPI-Linked Proteins; Humans; Kidney; Male; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Signal Transduction; Transforming Growth Factor beta1; Ureteral Obstruction

Renal interstitial fibrosis (RIF) is the leading cause of end-stage renal disease, partly because of the lack of effective treatments. Curcumin, the primary active ingredient in turmeric, reportedly exerts potent antifibrotic effects. This study investigated the effects of curcumin on RIF in unilateral ureteral obstruction (UUO) rats and characterized the underlying action mechanism. UUO rats were treated with curcumin for 7 and 14 d. Renal fibrosis was evaluated through haematoxylin-eosin staining, Masson staining, and type I and III collagen expression. Autophagy and mitochondria were observed through scanning electron microscopy. NLRP3 inflammasomes, mitochondria, and autophagy-related proteins were detected through Western blotting. Mitochondrial respiratory enzyme activity was assessed spectrophotometrically. Compared with UUO rats, renal fibrosis was attenuated and NLRP3 inflammasome activation was inhibited in curcumin-treated rats. Furthermore, mitochondrial dysfunction was ameliorated and the LC3B/LC3A ratio and Beclin-1 expression were increased in curcumin-treated rats. Additionally, curcumin inhibited the PI3K/AKT/mTOR pathway. These results indicate that curcumin is a promising treatment agent for RIF, and its antifibrotic effects may be mediated by the inhibition of NLRP3 inflammasome activity through the regulation of autophagy and protection of mitochondrial function in UUO rats.

Topics: Animals; Autophagy; Curcumin; Disease Models, Animal; Fibrosis; Humans; Inflammasomes; Kidney Failure, Chronic; Kidney Tubules; Male; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Ureteral Obstruction

Renal interstitial fibrosis (RIF) is characterized by the accumulation of inflammatory cytokines and epithelial-mesenchymal transition (EMT). Curcumin exerts antifibrogenic, anti-inflammatory and antiproliferative effects.. To explore the mechanisms underlying the effects of curcumin on RIF.. Eight-week-old male C57BL/6 mice were intragastrically administered curcumin (50 mg/kg/day) for 14 days after undergoing unilateral ureteral obstruction (UUO) operations. Renal function (blood urea nitrogen [BUN] and serum creatinine [Scr]) and inflammatory cytokine levels were tested using colorimetric assays and ELISA, respectively. EMT markers were evaluated through immunohistochemistry, western blotting and qPCR. Transforming growth factor beta 1 (TGF-β1; 10 ng/mL) and lipopolysaccharides (LPS; 100 ng/mL) were used to stimulate EMT and an inflammatory response in human renal proximal tubular epithelial (HK-2) cells, respectively, for further investigation.. Curcumin repressed EMT and the inflammatory response by inhibiting the TLR4/NF-κB and PI3K/AKT pathways, demonstrating its potential utility in RIF treatment.

Topics: Animals; Anti-Inflammatory Agents; Blood Urea Nitrogen; Cell Line; Curcumin; Disease Models, Animal; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Kidney Diseases; Male; Mice, Inbred C57BL; NF-kappa B; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Toll-Like Receptor 4; Ureteral Obstruction

Renal fibrosis is the common final outcome of nearly all progressive chronic kidney diseases (CKD) that eventually develop into end-stage renal failure, which threatens the lives of patients. Currently, there are no effective drugs for the treatment of renal fibrosis. However, studies have shown that certain plant natural products have a fibrosis-alleviating effect. Thus, we have screened a large number of natural products for their ability to protect against renal fibrosis and found that bisdemethoxycurcumin has a good therapeutic effect in renal fibrosis according to the data obtained in a mouse model of unilateral ureteral obstruction (UUO). The results indicate that bisdemethoxycurcumin can efficiently attenuate renal fibrosis induced by UUO. Additional studies of the bisdemethoxycurcumin mechanism of action in the treatment of renal fibrosis demonstrated that the therapeutic effect of bisdemethoxycurcumin is mediated by the specific induction of fibroblast apoptosis at a concentration of 20 μM. bisdemethoxycurcumin can efficiently protect against renal fibrosis both in vitro and in vivo. This discovery will provide new ideas for renal fibrosis treatment in clinics and a new direction for the development of effective drug therapy of renal fibrosis.

Topics: Animals; Apoptosis; Biological Products; Cell Line; Curcumin; Diarylheptanoids; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Humans; Kidney; Male; Mice; Protective Agents; Renal Insufficiency, Chronic; Ureteral Obstruction; Urinary Tract

Tumor necrosis factor α (TNF-α) is implicated in the pathophysiology of renal obstruction through its interactions with two TNF-α receptors: TNFR1 and TNFR2. Activation of TNFR1 leads to the recruitment of the adaptor TNFR-associated death domain protein (TRADD), which binds the Ser/Thr kinase receptor-interacting protein (RIP) and TNFR-associated factors 2 (TRAF2). This TRADD-RIP-TRAF complex causes activation of the antiapoptotic pathway and inhibits caspase 8 activation. Meanwhile, activation of TNFR2 leads to depletion of TRAF2 and enhancement of the apoptotic pathway. Curcumin, the major component found in turmeric spice, has been reported to possess a protective role against renal injury elicited by unilateral ureteral obstruction (UUO). The present study aimed mainly to address the cytoprotective role of curcumin-rich diet (5% w/w) on the apoptotic pathway induced by UUO in rats after 30 d of ligation.. The levels of mRNA for TNFR1, TNFR2, RIP, TRAF2, and caspase 8 were measured by reverse transcription-polymerase chain reaction. The levels of TNF-α was determined by ELISA. Kidney sections were exposed to histologic and morphometric studies.. Administration of curcumin decreased TNF-α, TNFR2, and caspase 8 without affecting TNFR1 levels. The gene expression levels of the antiapoptotic molecules RIP and TRAF2 were increased.. The cytoprotective role of curcumin relies on its ability to decrease the TNFR2 mRNA and enhance the antiapoptotic molecules RIP and TRAF2 to decrease the apoptotic pathway via decreasing the caspase 8.

Topics: Animals; Apoptosis; Caspase 8; Curcuma; Curcumin; Disease Models, Animal; Gene Expression Regulation; Kidney; Male; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; RNA, Messenger; TNF Receptor-Associated Factor 2; Ureteral Obstruction

Curcuma aromatica oil is a traditional herbal medicine demonstrating protective and anti-fibrosis activities in renal fibrosis patients. However, study of its mechanism of action is challenged by its multiple components and multiple targets that its active agent acts on.. Nuclear magnetic resonance (NMR)-based metabonomics combined with clinical chemistry and histopathology examination were performed to evaluate intervening effects of Curcuma aromatica oil on renal interstitial fibrosis rats induced by unilateral ureteral obstruction. The metabolite levels were compared based on integral values of serum 1H NMR spectra from rats on 3, 7, 14, and 28 days after the medicine administration. Time trajectory analysis demonstrated that metabolic profiles of the agent-treated rats were restored to control levels after 7 days of dosage. The results confirmed that the agent would be an effective anti-fibrosis medicine in a time-dependent manner, especially in early renal fibrosis stage. Targeted metabolite analysis showed that the medicine could lower levels of lipid, acetoacetate, glucose, phosphorylcholine/choline, trimethylamine oxide and raise levels of pyruvate, glycine in the serum of the rats. Serum clinical chemistry and kidney histopathology examination dovetailed well with the metabonomics data.. The results substantiated that Curcuma aromatica oil administration can ameliorate renal fibrosis symptoms by inhibiting some metabolic pathways, including lipids metabolism, glycolysis and methylamine metabolism, which are dominating targets of the agent working in vivo. This study further strengthens the novel analytical approach for evaluating the effect of traditional herbal medicine and elucidating its molecular mechanism.

Topics: Animals; Curcuma; Fibrosis; Kidney Diseases; Male; Metabolomics; Plant Oils; Proton Magnetic Resonance Spectroscopy; Rats, Sprague-Dawley; Time Factors; Ureteral Obstruction

To investigate the effect of curcumin on the alterations in renal functional parameters following reversible unilateral ureteric obstruction in the rat.. Wistar rats underwent reversible left ureteric obstruction for 72 h. The group Cm (n = 7) received oral curcumin (200 mg/kg/day), whereas the Vx group (n = 8) had only a vehicle.. Ureteric obstruction caused a significant increase in the serum tumour necrosis factor α in both groups. However, the post-obstruction level in the Cm group was significantly lower than in the Vx group. In the Vx group, the glomerular filtration rate, renal blood flow, urine volume and urinary sodium excretion in the left obstructed kidney were significantly lower than those in the right kidney, but the fractional excretion of sodium was comparable in the 2 groups. The left kidney in the Cm group behaved similar to that in the Vx group. Moreover, there was no difference in any variable when comparing the right and left kidneys among the groups.. Curcumin appears to have no significant protective effect on the haemodynamic or tubular glomerular functions when measured as early as 3 days following reversible ureteric obstruction despite the amelioration in some of the indicators of renal injury.

Topics: Animals; Curcumin; Glomerular Filtration Rate; Hemodynamics; Kidney; Male; Rats; Rats, Wistar; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ureteral Obstruction

To observe the effects of curcumin on the epithelial mesenchymal transition (EMT) and TGF-beta/Smads signal pathway in unilateral ureteral obstruction (UUO) rats.. UUO rat model was established. Rats were divided into the sham-operation group, the model group, the 1st curcumin group, and the 2nd curcumin group, respectively. From the 2nd day after surgery, rats of the 1st curcumin group were administrated with curcumin by gastrogavage at the daily dose of 100 mg/kg. From the 10th day after surgery, rats of the 2nd curcumin group were administrated with curcumin by gastrogavage at the daily dose of 100 mg/kg. Equal volume of normal saline was given to rats by gastrogavage in the sham-operation group and the model group. On the 28th day after surgery rats were killed. The renal tissues of the obstructed side were taken out. The distribution of mice alpha-smooth muscle actin (alpha-SMA) and E-cadherin expressions were observed using immunohistochemical method. Transforming growth factor-beta 1 (TGF-beta 1), P-Smad2, P-Smad3, and Smad7 expressions were detected by Western blot. TGF-beta 1, transforming growth factor-beta receptor I (TbetaRI), collagen-I (Col-I), and collagen-III (Col-III) mRNA expressions were detected by Real-time fluorescent quantitative PCR.. alpha-SMA expressions were obviously enhanced, E-cadherin expressions obviously weakened, the protein expression levels of P-Smad2 and P-Smad3, protein and mRNA expression levels of TGF-beta 1, TbetaRI mRNA, Col-I mRNA, and Col-III mRNA obviously up-regulated, Smad7 protein expressions obviously decreased (all P<0.01) in the renal tissues of rats in the UUO group. In the 1st curcumin group and the 2nd curcumin group, the protein expressions of alpha-SMA, P-Smad2, P-Smad3, and TGF-beta 1; mRNA expression levels of TGF-beta 1, TbetaRI mRNA, Col-I, and Col-III obviously decreased (P<0.05, P< 0.01), while the protein expressions of E-cadherin and Smad7 obviously increased (P<0.05, P<0.01).. Curcumin could intervene several sites of the TGF-beta/Smads signal transduction pathway of UUO rats, inhibit the occurrence of EMT of renal tubular epithelial cells, thus attenuating the tubulo-interstitial fibrosis.

Topics: Animals; Curcumin; Epithelial-Mesenchymal Transition; Kidney Tubules; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Ureteral Obstruction

The unilateral ureteral obstruction (UUO) model of renal injury in rat is characterized by nuclear factor kappaB (NF-kappaB) activation and tumour necrosis factor alpha (TNF-alpha) production, which induces apoptosis via activation of caspase 8 resulting in cell death. Curcumin, the major component found in turmeric spice, has been reported to provide protection against fibrosis and apoptosis elicited by UUO. This study examined the effects of a turmeric-based diet (5% w/w) on the apoptotic pathway induced by UUO in rats after 30 days of ligation. Administration of a turmeric-based diet demonstrated a significant decrease (P<0.05) in mRNA expression of TNF-alpha and caspase 8, but not NF-kappaB, expression, which may contribute to the protective role of the turmeric-based diet. We conclude that a turmeric-based diet can delay apoptosis without modulating NF-kappaB, so as not to sensitize the mesangial cells to the apoptotic stimuli.

Topics: Animals; Apoptosis; Blood Urea Nitrogen; Caspase 8; Creatinine; Curcuma; Diet; Disease Models, Animal; Electrophoresis, Agar Gel; Fibrillar Collagens; Kidney Cortex; Kidney Tubules; Male; NF-kappa B; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha; Ureteral Obstruction

To test whether curcumin has a protective action against interstitial inflammation and the development of renal fibrosis in obstructive nephropathy. We also tested whether inhibition of nuclear factor kappa-B (NF-kappaB) and activator protein-1 (AP-1) by curcumin is involved in these mechanisms.. Adult male rats underwent unilateral ureteral obstruction. The rats were treated with curcumin (200 mg/kg/day or 800 mg/kg/day), NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC; 200 mg/kg/day), or vehicle by gavage. Sham-operated rats served as controls. Seven days after unilateral ureteral obstruction, the activity of NF-kappaB and AP-1 was examined by electrophoretic mobility shift assay using nuclear protein extracts from the renal cortex. Gene expression of chemokines and pro-fibrotic molecules was determined by real-time reverse transcriptase-polymerase chain reaction. Macrophage infiltration and collagen III accumulation in the cortical interstitium was examined immunohistochemically.. Both curcumin and PDTC significantly attenuated interstitial macrophage influx and renal fibrosis. Ureteral occlusion activated both NF-kappaB and AP-1-DNA binding. Curcumin and PDTC significantly inhibited NF-kappaB activity, but not AP-1. Gene expression of chemokines and pro-fibrotic molecules was upregulated in unilateral ureteral obstruction that was attenuated by either curcumin or PDTC.. Curcumin protected against the renal interstitial inflammation and fibrosis elicited by ureteral occlusion. Inhibition of the NF-kappaB-dependent pathway is at least in part involved in the mechanisms, but AP-1 inhibition is unlikely to be involved in the beneficial effects of curcumin.

Topics: Animals; Curcumin; Fibrosis; Kidney; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Transcription Factor AP-1; Ureteral Obstruction

Ureteral obstruction results in an injury response that can progress to irreversible renal fibrosis and tubular atrophy by apoptosis. The molecular events leading to apoptosis from obstruction are not well understood. We investigated the effect of bioflavonoids and angiotensin II inhibition on apoptotic and inflammatory gene expression in a model of unilateral ureteral obstruction (UUO).. Complete UUO was produced in rats by ureteral ligation. The rats were treated with dimethyl sulfoxide (control), enalapril, losartan, curcumin, or quercetin. The animals were killed on day 7 and both obstructed and contralateral unobstructed kidneys were harvested. Expression of the inflammatory chemokine monocyte chemotactic protein-1, apoptosis effector genes Fas and Fas ligand, and oxidative stress gene HO-1 was evaluated by reverse transcriptase-polymerase chain reaction.. Ureteral obstruction was associated with a 6.3-fold increase in monocyte chemotactic protein-1 expression compared with sham-operated rats (P = 0.01). Monocyte chemotactic protein-1 expression was severely attenuated in all other treatment groups (P <0.05). Similarly, Fas and Fas ligand expression were increased in control UUO kidneys compared with sham-operated ones (P <0.05). Fas gene expression was significantly inhibited by quercetin but not enalapril, losartan, or curcumin compared with the control. The induction of Fas ligand was attenuated in all treatment groups (P <0.05). HO-1 was expressed at low levels in both unobstructed and obstructed kidneys. Treatment with curcumin increased HO-1 expression fourfold (P <0.05).. The expression of apoptotic and chemokine genes is significantly upregulated in UUO. Bioflavonoids and angiotensin inhibitors are able to attenuate the expression of these genes and thus may be beneficial in renal protection.

Topics: Angiotensin II; Animals; Apoptosis; Chemokines; Curcumin; Disease Models, Animal; Flavonoids; Gene Expression; Kidney Diseases; Male; Nephritis; Quercetin; Rats; Rats, Sprague-Dawley; Ureteral Obstruction