Positive outcomes of phosphodiesterase type 5 inhibitor on histopathologic and biochemical changes induced by ureteral obstruction

SUMMARY OBJECTIVES: We examined the effects of tadalafil, one of the phosphodiesterase type 5 (PDE5) inhibitors, in a rat model of with partial and complete unilateral ureteral obstruction (UUO). METHODS: The rats were divided into 5 groups: sham (n=6), partial unilateral ureteral obstruction (PUUO, n=6), PUUO with tadalafil treatment (PUUO+T; Cialis, 10 mg/72 h, intragastric; Lilly, Indianapolis, Indiana, USA), complete unilateral ureteral obstruction (CUUO, n=6), and CUUO with tadalafil treatment (CUUO+T). RESULTS: Fifteen days after the UUO, the ureter presented changes in the layers of urothelium and significant infiltration of inflammatory cells in the PUUO and CUUO groups. Compared with the sham, PUUO and CUUO groups had severe increased inflammatory cell infiltration. The urothelial epithelium exhibited cell degeneration and loss because of the swollen, atrophic, and denuded epithelial cells in the PUUO and CUUO groups. In the PUUO+T and CUUO+T groups, the urothelium revealed less epithelial cell degeneration and loss. The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β) exhibited up-regulation in the PUUO and CUUO groups. The expression of TGF-β decreased positively correlated with that of α-SMA in the tadalafil therapy groups, PUUO+T and CUUO+T. CONCLUSION: The phosphodiesterase type 5 inhibitor's tadalafil reduced expressions of α-SMA and TGF-β in the obstructed ureters, measured by biochemical examinations. In addition, tadalafil decreased urothelium degeneration due to the decreased epithelial cell loss and inflammatory cell infiltration. Our results show that tadalafil prevents or slows down the onset of ureter inflammation and urothelial degeneration in rats with UUO.

RESUMO OBJETIVOS: Examinamos os efeitos do tadalafil em um dos inibidores da fosfodiesterase tipo 5 (PDE5) em um modelo de rato com obstrução ureteral unilateral parcial e completa (UUO). MÉTODOS: Os ratos foram divididos em cinco grupos: sham (n = 6), obstrução ureteral unilateral parcial (PUUO, n = 6), PUUO com tadalafil (PUUO T; Cialis, 10 mg/72 h, intragástrica; Lilly, Indianapolis, Indiana, EUA), completa obstrução ureteral unilateral (CUUO, n = 6) e CUUO com tratamento com tadalafil (CUUO T). RESULTADOS: Quinze dias após a UUO, o ureter apresentou alterações nas camadas de urotélio e infiltração significativa de células inflamatórias nos grupos PUUO e CUUO. Em comparação com os grupos sham, PUUO e CUUO, houve um aumento grave da infiltração de células inflamatórias. O epitélio urotelial exibiu degeneração e perda celular devido às células epiteliais inchadas, atróficas e desnudas nos grupos PUUO e CUUO. Nos grupos PUUO T e CUUO T, o urotélio revelou menor degeneração e perda de células epiteliais. Nós mostramos que a expressão da actina do músculo liso-α (α-SMA) e do fator de crescimento transformador-β (TGF-β) foram exibidas como sub-regulação nos grupos PUUO e CUUO. A expressão do TGF-β foi diminuída positivamente correlacionada com a da α-SMA nos grupos de terapia com tadalafil, PUUO T e CUUO T. CONCLUSÃO: O tadalafil do inibidor da fosfodiesterase tipo 5 reduziu as expressões α-SMA e TGF-β nos ureteres obstruídos, medidos por exames bioquímicos. Além disso, o tadalafil diminuiu a degeneração do urotélio devido à diminuição da perda de células epiteliais e da infiltração de células inflamatórias. Nossos resultados mostram que o tadalafil previne ou retarda o início da inflamação do ureter e degeneração urotelial em ratos com UUO.

Beneficial effects of Oltipraz, nuclear factor - erythroid - 2 - related factor 2 (Nrf2), on renal damage in unilateral ureteral obstruction rat model

ABSTRACT Introduction: We investigated whether Oltipraz (OPZ) attenuated renal fibrosis in a unilateral ureteral obstruction (UUO) rat model. Materials and Methods: We randomly divided 32 rats into four groups, each consisting of eight animals as follows: Rats in group 1 underwent a sham operation and received no treatment. Rats in group 2 underwent a sham operation and received OPZ. Rats in group 3 underwent unilateral ureteral ligation and received no treatment. Group 4 rats were subjected to unilateral ureteral ligation plus OPZ administration. Transforming growth factor beta-1 (TGF-β1), E-cadherin, nitric oxide (NO) and hydroxyproline levels were measured. Histopathological and immunohistochemical examinations were carried out. Results: TGF-β1, NO and E-cadherin levels in the UUO group were significantly higher than the sham group and these values were significantly different in treated groups compared to the UUO group. In rats treated with UUO + OPZ, despite the presence of mild tubular degeneration and less severe tubular necrosis, glomeruli maintained a better morphology when compared to the UUO group. Expressions of α-SMA in immunohistochemistry showed that the staining positivity decreased in the tubules of the OPZ-treated group. Conclusions: While the precise mechanism of action remains unknown, our results demonstrated that OPZ exerted a protective role in the UUO-mediated renal fibrosis rat model highlighting a promising therapeutic potency of Nrf2-activators for alleviating the detrimental effects of unilateral obstruction in kidneys.

Concomitant inhibition of renin angiotensin system and Toll-like receptor 2 attenuates renal injury in unilateral ureteral obstructed mice

BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.

Tratamento associado (clínico-cirúrgico) da fibrose retroperitoneal idiopática / Associated treatment (medical and surgical) of idiopathic retroperitoneal fibrosis

Os autores descrevem caso de paciente com fibrose retroperitoneal idiopática e revisão da patologia. Esta rara doença de etiologia incerta caracteriza-se por inflamação crônica do retroperitôneo, ocasionalmente aprisionando e obstruindo estruturas, notavelmente os ureteres. Trata-se de um paciente do sexo masculino, 45 anos, com dor em flanco esquerdo irradiada para testículo, em cólica, com piora progressiva. Feito o diagnóstico de fibrose retroperitoneal com compressão ureteral à esquerda (tomografia computadorizada do abdome), o paciente foi submetido a desobstrução ureteral com colocação de cateter duplo “J” e, posteriormente, a tratamento clínico com prednisona. Não houve regressão da massa fibrótica, mas melhora clínica quanto à dor e à ausência de novo episódio de obstrução ureteral. Os autores ressaltam a necessidade de suspeição da patologia descrita, mesmo sendo rara, pela possibilidade de complicações graves, se seu diagnóstico não for realizado e o tratamento não for instituído no tempo ideal

A case report of a patient with idiopathic retroperitoneal fibrosis (RPF) is described and the condition is reviewed as well. RPF is a rare disease of unclear etiology characterized by chronic retroperitoneal inflammation, which can entrap and obstruct retroperitoneal structures, notably ureters. A 45-year-old male patient presented with colic-likeleft flank pain irradiating to the testicle and progressively worsening. Retroperitoneal fibrosis with left ureteral compression was diagnosed in a abdominal computed tomography scan and the patient was submitted to reteral unblocking with insertion of a double-J catheter and then to clinical treatment with prednisone. Although there was no regression of the fibrotic mass, pain clinically relieved and no new ureteral obstruction episodes were seen. This case illustrates the importance of suspecting the above described condition. Although rare, RPF can potentially cause severe complications if it is not diagnosed and treated timely

Obstrucción unilateral de ureter post apendicectomía en el niño / Post appendicectomy unilateral obstruction of ureter in child

Un niño de 6 años y medio presenta un abdomen agudo quirúrgico 5 años después de una cirugía apendicular complicada. La gravedad clínica, por el cuadro de sepsis, exige una laparotomía exploradora inmediata, encontrando una masa retroperitoneal que resulta ser el riñón derecho con proceso infeccioso crónico, que se continúa con un uréter dilatado que termina cerrado en la vecindad de la zona ileocal. Este hallazgo no permite efectuar cirugía conservadora, por lo que se debe realizar nefroureterectomía derecha. La anatomía patológica muestra una pienefrosis, con daño avanzado del riñón contralateral sano, con hipertrofia compensadora. Egresa en 8 días, sin complicaciones precoces

Succesful treatment of idiopathic retroperitoneal fibrosis with steroids

Idiopathic retroperitoneal fibrosis [IRF] may cause ureteric obstruction with renal damage. Ureterolysis with intraperitonealization of the ureter is commonly used as primary treatment. We gave corticosteroids for two years to six patients, four males and two females, between 40 and 56 years of age. One of the patients is in his tenth month of treatment and another in the fourth month. Between 4 and 74 months [mean 40.4 months] after initiation of treatment, kidney function had improved, or was preserved in previously functioning renal units, and the patients were free from symptoms. We conclude that steroids may be used as primary treatment of IRF after histological or cytological diagnosis to exclude retroperitoneal malignancy. Steroids should also be part of the treatment strategy in patients with a more aggressive disease who may need surgery. Patients with IRF should be followed for the rest of their lives after discontinuation of steroid therapy