allopurinol and Ureteral-Obstruction

Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). Serum uric acid (SUA) levels in CKD stage 3-4 patients closely correlate with hyperuricemic nephropathy (HN) morbidity. New uric acid (UA)-lowering strategies are required to prevent CKD. The multiple-purpose connectivity map (CMAP) was used to discover potential molecules against HUA and renal fibrosis. We used HUA and unilateral ureteral occlusion (UUO) model mice to verify renoprotective effects of molecules and explore related mechanisms. In vitro experiments were performed in HepG2 and NRK-52E cells induced by UA. Esculetin was the top scoring compound and lowered serum uric acid (SUA) levels with dual functions on UA excretion. Esculetin exerted these effects by inhibiting expression and activity of xanthine oxidase (XO) in liver, and modulating UA transporters in kidney. The mechanism by which esculetin suppressed XO was related to inhibiting the nuclear translocation of hexokinase 2 (HK2). Esculetin was anti-fibrotic in HUA and UUO mice through inhibiting TGF-β1-activated profibrotic signals. The renoprotection effects of esculetin in HUA mice were associated with lower SUA, alleviation of oxidative stress, and inhibition of fibrosis. Esculetin is a candidate urate-lowering drug with renoprotective activity and the ability to inhibit XO, promote excretion of UA, protect oxidative stress injury, and reduce renal fibrosis.

Topics: Animals; Cell Nucleus; Disease Models, Animal; Down-Regulation; Fibrosis; Hep G2 Cells; Humans; Hyperuricemia; Kidney; Male; Membrane Transport Proteins; Mice; Mice, Inbred ICR; NADPH Oxidases; NF-E2-Related Factor 2; Oxidative Stress; Protein Transport; Transcriptome; Umbelliferones; Ureteral Obstruction; Uric Acid; Xanthine Oxidase

Renal interstitial fibrosis is the common pathway in progressive renal diseases, where oxidative stress promotes inflammation and macrophage infiltration. Febuxostat is a novel nonpurine xanthine oxidase (XO)-specific inhibitor for treating hyperuricemia. While some reports suggest a relationship between hyperuricemia and chronic kidney disease (CKD), the renoprotective mechanism of an XO inhibitor in CKD remains unknown. Recent reports have focused on XO as a source of oxidative stress.. Here, we investigate the potential of febuxostat to reduce fibrogenic and inflammatory responses in an established interstitial fibrosis model-unilateral ureteric obstruction (UUO). Male Sprague-Dawley rats were divided into three groups: sham-operated group, vehicle-treated UUO group, and febuxostat-treated UUO group.. Treatment with febuxostat diminished XO activity in obstructed kidneys, and suppressed nitrotyrosine, a marker of oxidative stress. Consequently, febuxostat inhibited early proinflammatory cytokine expression, followed by a reduction of interstitial macrophage infiltration. In addition, febuxostat suppressed transforming growth factor-β messenger RNA expression, thereby ameliorating smooth muscle alpha actin and type I collagen expression.. Our results provide evidence for the renoprotective action of febuxostat against the formation of interstitial fibrosis. A decrease in macrophage infiltration and interstitial fibrosis, along with a decrease of the oxidative stress marker, strongly suggests the existence of a causal relationship between them. Febuxostat may have therapeutic value in slowing or preventing interstitial fibrosis in patients with CKD.

Topics: Animals; Cell Movement; Cytokines; Disease Models, Animal; Febuxostat; Fibrosis; Kidney; Kidney Diseases; Macrophages; Male; Nephritis, Interstitial; Oxidative Stress; Rats; Rats, Sprague-Dawley; Thiazoles; Transforming Growth Factor beta; Ureteral Obstruction; Xanthine Oxidase

The aim of the present study was to evaluate whether relief of partial unilateral ureteral obstruction (PUUO) with or without antioxidant drug affect renal tissue malonedialdehyde (MDA) and glutathion (GSH) levels.. A total of 25 rats were used in this PUUO study. Partial unilateral ureteral obstruction was created by the burial of the upper one-third of the left ureter in the psoas muscle. The rats were sacrificed on 28th day following PUUO. Relief of the obstruction was performed twenty minutes before sacrifice by cutting the proximal ureter in reperfusion group. 50 mg/kg intraperitoneal allopurinol was administered 20 minutes before relief of obstruction in the antioxidant group. Renal tissue MDA and GSH levels were measured in both kidneys.. At the end of the study 5, 7 and 7 rats could only be interpreted in sham, reperfusion and antioxidant groups, respectively. While the mean left and right renal MDA and GSH levels were statistically different from each other in reperfusion group (P < 0.001), there were no significant differences in the sham (P > 0.05) and antioxidant (P > 0.05) group. Both the mean sham group left and right renal tissue MDA or GSH levels were significantly different from reperfusion group, but only the mean sham group left renal tissue MDA and right renal tissue GSH levels were not statistically different from antioxidant group (P < 0.05). The mean left or right renal MDA and GSH tissue levels of the antioxidant group were statistically different from reperfusion group (P < 0.05) except for the right renal tissue GSH level (P > 0.05).. Partial unilateral ureteral obstruction leads to oxidative injury by relief of obstruction in both kidneys. The antioxidant allopurinol has a beneficial effect on renal MDA and GSH levels in both kidneys.

Topics: Allopurinol; Animals; Disease Models, Animal; Free Radical Scavengers; Glutathione; Injections, Intraperitoneal; Kidney; Male; Malondialdehyde; Rats; Rats, Sprague-Dawley; Reperfusion; Ureteral Obstruction

Tissue homeostasis is determined by the balance between oxidants and antioxidants. Catalase is an important antioxidant enzyme regulating the level of intracellular hydrogen peroxide and hydroxyl radicals. The effect of catalase deficiency on renal tubulointerstitial injury induced by unilateral ureteral obstruction (UUO) has been studied in homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) compared with wild-type mice (C3H/AnLCs(a)Cs(a)). Complete UUO caused interstitial cell infiltration, tubular dilation and atrophy, and interstitial fibrosis with accumulation of type IV collagen in obstructed kidneys (OBK) of both mouse groups. However, the degree of injury showed a significant increase in OBK of acatalasemic mice compared with that of wild-type mice until day 7. The deposition of lipid peroxidation products including 4-hydroxy-2-hexenal, malondialdehyde, and 4-hydroxy-2-nonenal was severer in dilated tubules of acatalasemic OBK. Apoptosis in tubular epithelial cells significantly increased in acatalasemic OBK at day 4. Expression of caspase-9, a marker of mitochondrial pathway-derived apoptosis, increased in dilated tubules of acatalasemic mice. The level of catalase activity remained low in acatalasemic OBK until day 7 without compensatory upregulation of glutathione peroxidase activity. The data indicate that acatalasemia exacerbated oxidation of renal tissue and sensitized tubular epithelial cells to apoptosis in OBK of UUO. This study demonstrates that catalase deficiency enhanced tubulointerstitial injury and fibrosis in a murine model of UUO and thus supports the protective role of catalase in this model.

Topics: Acatalasia; Animals; Apoptosis; Body Weight; Catalase; Epithelial Cells; Fibrosis; Glutathione Peroxidase; Immunohistochemistry; In Situ Nick-End Labeling; Kidney Tubules; Male; Malondialdehyde; Mice; Mice, Inbred C3H; Mice, Knockout; Microscopy, Electron; Nephritis, Interstitial; Organ Size; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Ureteral Obstruction; Xanthine Oxidase

The complex series of pathophysiologic alterations associated with obstruction nephropathy includes renal ischemia. Free-radical production follows relief of obstruction. We sought to determine whether free radicals caused additional reduction in blood flow after relief of obstruction.. In White-Landrace pigs, the left ureter was divided 6 cm distal to the ureteropelvic junction, and a nephrostomy tube was passed into the renal pelvis and exteriorized. A catheter was placed in the renal vein and exteriorized. Mean renal blood flow was measured before manipulation and during and after 6 hours of obstruction in animals receiving (N = 7) or not receiving (N = 7) allopurinol. The control groups were not subjected to ureteral obstruction and received (N = 7) or did not receive (N = 7) allopurinol. Free radicals in venous blood were measured by the Fox-1 assay for lipid peroxidation.. After obstruction, renal blood flow declined significantly by the sixth hour (-28.73% +/- 1.81). The increase after relief of obstruction was only temporary, and by the third hour, the blood flow was again reduced (-20.14% +/- 2.67). Free radical production was significantly increased, with a peak of +24.63% being found 60 minutes after relief of obstruction. Allopurinol prevented free radical production after relief of obstruction and was associated with a return of blood flow to baseline values.. Free radicals contribute to renal blood flow reduction after relief of ureteral obstruction. Functional impairment may be preventable by free radical blockade, but further studies are required to confirm this hypothesis.

Topics: Allopurinol; Animals; Female; Free Radical Scavengers; Free Radicals; Ischemia; Renal Circulation; Renal Veins; Reperfusion Injury; Swine; Ureteral Obstruction

Topics: Allopurinol; Humans; Kidney Diseases; Male; Middle Aged; Renal Dialysis; Ureteral Obstruction; Uric Acid

Topics: Allopurinol; Cyclophosphamide; Female; Humans; Lymph Node Excision; Lymphoma, Non-Hodgkin; Middle Aged; Prednisolone; Prognosis; Ureteral Obstruction; Vincristine

An obstructing uric acid calculus was successfully managed by dissolution in situ. The methods used are described in detail. Perhaps not applicable in all cases, the ease of the procedure makes it worth considering especially in patients at high risk for open operative intervention.

Topics: Allopurinol; Bicarbonates; Female; Humans; Hydrogen-Ion Concentration; Infusions, Parenteral; Middle Aged; Radiography; Therapeutic Irrigation; Ureteral Calculi; Ureteral Obstruction; Uric Acid; Urinary Catheterization

Topics: Acute Kidney Injury; Adult; Allopurinol; Diuretics; Humans; Renal Dialysis; Ureteral Obstruction; Uric Acid; Urinary Catheterization

Topics: Allopurinol; Colchicine; Creatinine; Gout; Humans; Kidney Calculi; Male; Middle Aged; Phenylbutazone; Sulfadiazine; Ureteral Obstruction; Uric Acid; Urography