Unilateral Ureteral Obstruction Injury Research Articles

Astragaloside IV ameliorates renal fibrosis via the inhibition of mitogen-activated protein kinases and antiapoptosis in vivo and in vitro.

Apoptosis of renal tubular cells plays a crucial role in renal fibrosis. Astragaloside IV (AS-IV), a compound extracted from Radix Astragali, has been shown to inhibit renal tubular cell apoptosis induced by high glucose, but its role in preventing chronic renal fibrosis as well as the underlying molecular mechanisms involved still remain obscure. In this study, human kidney tubular epithelial cells induced by transforming growth factor-β1 (TGF-β1) were used to investigate the protective role of AS-IV in antifibrosis. As an in vivo model, mice subjected to unilateral ureteral obstruction (UUO) were administered AS-IV (20 mg/kg) by intraperitoneal injection for 7 days. AS-IV significantly alleviated renal mass loss and reduced the expression of α-smooth muscle actin, fibronectin, and collagen IV both in vitro and in vivo, suggesting that this compound functions in the inhibition of renal tubulointerstitial fibrosis. Furthermore, transferase-mediated dUTP nick-end labeling assay results both in vivo and in vitro showed that AS-IV significantly attenuated both UUO and TGF-β1-induced cell apoptosis and prevented renal tubular epithelial cell injury in a dose-dependent manner. Western blotting results also revealed that the antiapoptotic effect of AS-IV was reflected in the inhibition of caspase-3 activation, which might be mediated primarily by the downregulation of mitogen-activated protein kinase effectors phospho-p38 and phospho-c-Jun N-terminal kinase. These data infer that AS-IV effectively attenuates the progression of renal fibrosis after UUO injury and may have a promising clinical role as a potential antifibrosis treatment in patients with chronic kidney disease.

The Selective A3AR Antagonist LJ-1888 Ameliorates UUO-Induced Tubulointerstitial Fibrosis

Adenosine in the normal kidney significantly elevates in response to cellular damage. The renal A3 adenosine receptor (A3AR) is up-regulated under stress, but the therapeutic effects of A3AR antagonists on chronic kidney disease are not fully understood. The present study examined the effect of LJ-1888 [(2R,3R,4S)-2-[2-chloro-6-(3-iodobenzylamino)-9H-purine-9-yl]-tetrahydrothiophene-3,4-diol], a newly developed potent, selective, species-independent, and orally active A3AR antagonist, on unilateral ureteral obstruction (UUO)-induced renal fibrosis. Pretreatment with LJ-1888 inhibited UUO-induced fibronectin and collagen I up-regulation in a dose-dependent manner. Masson's trichrome staining confirmed that LJ-1888 treatment effectively reduced UUO-induced interstitial collagen accumulation. Furthermore, delayed administration of LJ-1888 showed an equivalent therapeutic effect on tubulointerstitial fibrosis to that of losartan. Small-interfering A3AR transfection effectively inhibited transforming growth factor-β1 (TGF-β1)-induced fibronectin and collagen I up-regulation in proximal tubular cells similar to LJ-1888, confirming that the renoprotective effect of LJ-1888 resulted from A3AR blockade. UUO- or TGF-β1-induced c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation decreased significantly after LJ-1888 administration. A3AR blockade reduced UUO- or TGF-β1-induced up-regulation of lysyl oxidase, which induces cross-linking of extracellular matrix, suggesting that LJ-1888 may also regulate extracellular matrix accumulation via post-translational regulation. In conclusion, the present data demonstrate that the A3AR antagonist, LJ-1888, blocked the development and attenuated the progression of renal fibrosis, and they suggest that LJ-1888 may become a new therapeutic modality for renal interstitial fibrosis.

Blocking the Class I Histone Deacetylase Ameliorates Renal Fibrosis and Inhibits Renal Fibroblast Activation via Modulating TGF-Beta and EGFR Signaling

BackgroundHistone deacetylase (HDAC) inhibitors are promising anti-fibrosis drugs; however, nonselective inhibition of class I and class II HDACs does not allow a detailed elucidation of the individual HDAC functions in renal fibrosis. In this study, we investigated the effect of MS-275, a selective class I HDAC inhibitor, on the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO) and activation of cultured renal interstitial fibroblasts.Methods/FindingsThe UUO model was established by ligation of the left ureter and the contralateral kidney was used as a control. At seven days after UUO injury, kidney developed fibrosis as indicated by deposition of collagen fibrils and increased expression of collagen I, fibronectin and alpha-smooth muscle actin (alpha-SMA). Administration of MS-275 inhibited all these fibrotic responses and suppressed UUO-induced production of transforming growth factor-beta1 (TGF-beta), increased expression of TGF-beta receptor I, and phosphorylation of Smad-3. MS-275 was also effective in suppressing phosphorylation and expression of epidermal growth factor receptor (EGFR) and its downstream signaling molecule, signal transducer and activator of transcription-3. Moreover, class I HDAC inhibition reduced the number of renal tubular cells arrested in the G2/M phase of the cell cycle, a cellular event associated with TGF-beta1overproduction. In cultured renal interstitial fibroblasts, MS-275 treatment inhibited TGF-beta induced phosphorylation of Smad-3, differentiation of renal fibroblasts to myofibroblasts and proliferation of myofibroblasts.Conclusions and SignificanceThese results demonstrate that class I HDACs are critically involved in renal fibrogenesis and renal fibroblast activation through modulating TGF-beta and EGFR signaling and suggest that blockade of class I HDAC may be a useful treatment for renal fibrosis.

Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

We recently showed that suramin treatment prevents the onset of renal fibrosis in a model of obstructive nephropathy induced by unilateral ureteral obstruction (UUO). In this study, we further assessed the effect of delayed administration of suramin on the progression of tubulointerstitial fibrosis. Mice were given a single dose of suramin at 20 mg/kg starting at day 3 of obstruction, and kidneys were harvested after an additional 7 or 14 days of obstruction. Suramin completely blocked further increase in expression of type I collagen and fibronectin and largely suppressed expression of α-smooth muscle actin (α-SMA) in both treatment groups. UUO injury induced phosphorylation of Smad-3, a key mediator of transforming growth factor-β (TGF-β) signaling, epidermal growth factor receptor, and platelet-derived growth factor receptor after 3 days and further increased at 10 days after UUO injury. When suramin was administered at 3 days after obstruction, phosphorylation of these molecules was not further increased in the obstructed kidney. Suramin treatment also inhibited activation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1 and 2, two signaling pathways associated with renal fibrogenesis. Furthermore, delayed application of suramin suppressed TGF-β1-induced expression of α-SMA and fibronectin in cultured renal interstitial fibroblasts. These results indicate that administration of suramin is effective in attenuating the progression of renal fibrosis after injury and suggest the potential clinical application of suramin as an antifibrotic treatment in patients with chronic kidney disease.

Preventive effects of propofol and ketamine on renal injury in unilateral ureteral obstruction

The aim of the present study was to investigate the preventive effects of propofol and ketamine as anesthetics on renal injury in unilateral ureteral obstruction (UO). Twenty-four male New Zealand white rabbits were randomly assigned to four groups of six rabbits each. Anesthesia was induced and maintained with propofol in groups 1 and 2 and with ketamine in groups 3 and 4. Groups 2 and 4 received complete left ureteral ligation. Groups 1 and 3 (control groups) underwent an identical surgical procedure without ureteral ligation. At 14 days of obstruction, animals were sacrificed and ipsilateral kidneys were removed for determination of tissue nitric oxide (NO) levels and immunohistochemical evaluation of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and apoptosis protease-activating factor 1 (APAF-1). Between groups 1 and 3, there were no differences in tissue NO levels and eNOS, iNOS, and APAF-1 expressions. iNOS and APAF-1 expressions were at the mild to moderate levels in group 2, but these parameters were markedly increased in group 4 at 14 days of obstruction. Also, elevated expression of iNOS was accompanied by a high NO production in group 4 compared with group 2. Although eNOS expressions were increased in both groups 2 and 4, there were no significant differences between these groups. Propofol as an anesthetic agent may attenuate NO-induced renal tubular cell apoptosis by downregulating the expression of iNOS in an animal model of unilateral UO.

Sulfasalazine reduces inflammatory renal injury in unilateral ureteral obstruction

The purpose of this study was to test whether sulfasalazine has a protective action against interstitial inflammation and the development of renal fibrosis in obstructive nephropathy. Female rats were subjected to a sham (n = 10) or unilateral ureteral obstruction (UUO, n = 30). UUO was induced in rats by ligating the left ureter. Three days after operation, rats subjected to UUO were randomized to receive tretment with either sulfasalazine (100 mg/kg) or vehicle every day for the last 7 days of the experiment. At 10 days following UUO, the obstructed kidney exhibited tubulointerstitial injury and leukocyte infiltration (mainly monocytes) that were associated with high levels of reactive oxygen species, cytokines, transforming growth factor (TGF)-beta1, myeloperoxidase (MPO), and lipid peroxidation. Ten days after UUO, the obstructed kidney was also associated with increased nuclear factor kappa beta (NF-kappabeta) expression in saline-treated rats. Compared with sham-operated rats, UUO rat kidneys showed lower concentrations of antioxidant enzymes in the obstructed kidney tissue. All of these changes were significantly attenuated by treatment with sulfasalazine in the obstructed kidney. Sulfasalazine protected against the renal interstitial inflammation and tissue damage elicited by ureteral occlusion. Inhibition of the NF-kappabeta-dependent pathway and inflammatory response and oxidative stress inhibition is likely to be involved in the beneficial effects of sulfasalazine.

301: Adrenomedullin Increases Renal Nitric Oxide (NO) Production and Ameliorates Renal Injury in Unilateral Ureteral Obstruction (UUO)

You have accessJournal of UrologyPodium 9, Sunday, May 20, 2007 10:00 am - 12:00 pm1 Apr 2007301: Adrenomedullin Increases Renal Nitric Oxide (NO) Production and Ameliorates Renal Injury in Unilateral Ureteral Obstruction (UUO) Keiichi Ito, Tomohiko Asano, Takako Asano, Kaori Seta, Yasunori Mizuguchi, and Masamichi Hayakawa Keiichi ItoKeiichi Ito More articles by this author , Tomohiko AsanoTomohiko Asano More articles by this author , Takako AsanoTakako Asano More articles by this author , Kaori SetaKaori Seta More articles by this author , Yasunori MizuguchiYasunori Mizuguchi More articles by this author , and Masamichi HayakawaMasamichi Hayakawa More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)30566-4AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "301: Adrenomedullin Increases Renal Nitric Oxide (NO) Production and Ameliorates Renal Injury in Unilateral Ureteral Obstruction (UUO)." The Journal of Urology, 177(4S), p. 101 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 177Issue 4SApril 2007Page: 101 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Keiichi Ito More articles by this author Tomohiko Asano More articles by this author Takako Asano More articles by this author Kaori Seta More articles by this author Yasunori Mizuguchi More articles by this author Masamichi Hayakawa More articles by this author Expand All Advertisement PDF downloadLoading ...

Review : Biochemical-molecular markers in unilateral ureteral obstruction

Congenital obstructive nephropathy is the primary cause of end-stage renal disease in children. Rapid diagnosis and initiation of the treatment are vital to preserve function and/or to slow down renal injury. Obstructive uropathy effects -decline in the plasmatic renal flow and glomerular filtration rate, interstitial infiltrate of leukocytes, significant decrease of the urine concentration, loss of the capacity to concentrate urine as well as fibrosis and apoptosis- are a consequence of a variety of factors that work in complex ways and are still not fully understood. Mediators as angiotensin II, transforming growth factor-beta (TGF-beta) and nitric oxide (NO) have been implicated in congenital obstructive nephropathy. The renin-angiotensin system is regulated in different ways, affecting both renal structure and function, and that it in turn depends upon the duration of the obstruction. On the other hand, the role of nitric oxide in renal injury remains somewhat controversial due to the fact that it can exert opposite effects such as cytoprotective and prooxidant / proapoptotic efects as well as proinflammatory and anti-inflammatory effects. In addition, reactive oxidative species (ROS) might contribute to the progression of renal disease. During unilateral ureteral obstruction induced uncoordinated and aberrant growth may lead to the loss of cellular phenotype and apoptosis. Promoting inflammatory responses, the oxidizers can regulate the adherence of certain molecules and proinflammatory mediators, transcription factors and fibrogenic cytokines, that are clearly involved in the progression of renal disease. The congenital obstructive nephropathy is characterized by tubular atrophy, cellular proliferation, apoptosis and fibrosis; immature kidney is more susceptible than adult kidney to showing the above mentioned alterations. Apoptosis seems to be the principal mechanism that leads to tubular atrophy during the neonatal unilateral ureteral obstruction (UUO). Considering the significant role of the apoptosis in UUO, we believe of big interest the study of the regulatory factors of apoptosis in the renal obstruction neonatal. The complex biochemical and molecular events during the development, maintenance and progression of the renal injury in unilateral ureteral obstruction require further major studies to better understand the alterations mentioned above.

Novel Nuclear Factor κB Activation Inhibitor Prevents Inflammatory Injury in Unilateral Ureteral Obstruction

We determined whether the novel nuclear factor kappa B activation inhibitor dehydroxymethylepoxyquinomicin (DHMEQ), which is derived from epoxyquinomicin C, affects renal inflammatory responses in unilateral ureteral obstruction. DHMEQ (8 mg./kg.) was administered to rats 1 day after unilateral ureteral obstruction and every day thereafter. Kidneys were harvested at day 7 after unilateral ureteral obstruction. Tissue nuclear factor kappa B activity and transforming growth factor-beta were determined by electrophoretic mobility shift assay and bioassay using mink lung epithelial cells, respectively. Renal tubular proliferation and apoptosis were detected by immunostaining proliferating cellular nuclear antigen and the TUNEL (Intergen, Purchase, New York) assay, respectively. Leukocyte infiltration was detected by immunostaining for CD45. Fibrosis was assessed by measuring tissue hydroxyproline content. Unilateral ureteral obstruction for 7 days significantly activated nuclear factor kappa B, induced tubular apoptosis, proliferation and interstitial fibrosis in the obstructed kidney of the control group compared with their unobstructed counterparts (30.3 +/- 4.5 nuclei per high power field versus 1.7 +/- 0.4, 25.7 +/- 3.3 nuclei per high power field versus 3.2 +/- 0.4 and 6.2 +/- 0.3 micromol. hydroxyproline per gm. tissue versus 3.4 +/- 0.1, respectively). Conversely daily administration of DHMEQ (8 mg./kg.) significantly inhibited nuclear factor kappa B activation and decreased mean tubular apoptosis (9.5 +/- 2.1 nuclei per high power field), proliferation (10.2 +/- 2.4 nuclei per high power field) and interstitial fibrosis (4.9 +/- 0.4 micromol. hydroxyproline per gm. tissue) in the obstructed kidney. Specific inhibition of nuclear factor kappa B can prevent inflammatory renal responses, suggesting that targeting nuclear factor kappa B activation may be feasible for preventing inflammatory kidney diseases.

Alpha-tocopherol modulates lipoprotein cytotoxicity in obstructive nephropathy.

Oxidative stress in unilateral ureteral obstruction (UUO) contributes to the development of glomerular and tubulointerstitial lesions. The present study investigated whether oxidized low-density lipoprotein (oLDL) contributes to the pathogenesis of kidney injury in UUO, and whether alpha-tocopherol modulates such cytotoxicity and promotes repair. Male Sprague-Dawley rats weighing 100-125 g were assigned to three groups of 6 animals each: (1) sham, regular chow; (2) UUO, regular chow; and (3) UUO, alpha-tocopherol supplementation. We found a significant increase in the level of oxidative stress in the UUO group as measured by malondialdehyde (MDA) content in both plasma and kidneys. The LDL isolated from this group was cytotoxic to rat mesangial cells. The level of oxidation and cytotoxicity was significantly reduced when animals were treated with alpha-tocopherol. Plasma cholesterol concentration, kidney MDA, and transforming growth factor beta1 mRNA expression were all significantly increased in the UUO animals, and partially reduced in alpha-tocopherol-treated animals. Our data suggest that oxidative modification of LDL is associated with the renal injury in UUO. Taken together, our data support the concept that alpha-tocopherol can modulate LDL oxidation and its cytotoxic effects on rat mesangial cells in vitro.

Report of ENMC workshop on the limb-girdle muscular dystrophies.

We recently showed that suramin treatment prevents the onset of renal fibrosis in a model of obstructive nephropathy induced by unilateral ureteral obstruction (UUO). In this study, we further assessed the effect of delayed administration of suramin on the progression of tubulointerstitial fibrosis. Mice were given a single dose of suramin at 20 mg/kg starting at day 3 of obstruction, and kidneys were harvested after an additional 7 or 14 days of obstruction. Suramin completely blocked further increase in expression of type I collagen and fibronectin and largely suppressed expression of α-smooth muscle actin (α-SMA) in both treatment groups. UUO injury induced phosphorylation of Smad-3, a key mediator of transforming growth factor-β (TGF-β) signaling, epidermal growth factor receptor, and platelet-derived growth factor receptor after 3 days and further increased at 10 days after UUO injury. When suramin was administered at 3 days after obstruction, phosphorylation of these molecules was not further increased in the obstructed kidney. Suramin treatment also inhibited activation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1 and 2, two signaling pathways associated with renal fibrogenesis. Furthermore, delayed application of suramin suppressed TGF-β1-induced expression of α-SMA and fibronectin in cultured renal interstitial fibroblasts. These results indicate that administration of suramin is effective in attenuating the progression of renal fibrosis after injury and suggest the potential clinical application of suramin as an antifibrotic treatment in patients with chronic kidney disease.