The Effect of Tadalafil on Renal Fibrosis Induced by Ureteral Obstruction / Efecto del Tadalafil en la Fibrosis Renal Inducida por Obstrucción Uretral

ABSTRACT Objective: It has been reported that phosphodiesterase-5 (PDE-5) inhibitors improve kidney function during acute and chronic renal failure. This study aimed to determine the possible therapeutic effects of tadalafil, a specific PDE-5 inhibitor, on renal fibrosis induced by unilateral ureteral obstruction (UUO). Methods: Male Sprague-Dawley rats were used and randomly divided into three groups (n = 6) as sham-operated, UUO and tadalafil-treated (10 mg/72 hours, ig) UUO (UUO+T) groups. Unilateral ureteral obstruction was induced by complete ligation of the left ureter and 14 days after surgery creatinine clearance, urinary cyclic guanosine monophosphate (cGMP), renal alpha-smooth muscle actin (α-sma) and transforming growth factor βeta (TGF-β) levels, as well as histologic changes, were observed in all the animals. Results: Unilateral ureteral obstruction-induced renal fibrosis was confirmed by increased α-sma level, collagen deposition, tubular dilation, inflammatory cell infiltration and necrosis. An increased renal TGF-β level and decreased urinary cGMP level was also observed in obstructed animals in addition to reduced creatinine clearance. Tadalafil treatment, which restored the animals 'urinary cGMP level, significantly attenuated the fibrotic changes and TGF-β increase in their kidneys. Conclusion: This study suggests that tadalafil treatment ameliorates renal fibrosis by reducing TGF-β expression and may have important clinical relevance since tadalafil is currently used clinically to treat erectile dysfunction and pulmonary hypertension.

RESUMEN Objetivo: Se ha reportado que los inhibidores de la fosfodiesterasa-5 (PDE-5) mejoran las funciones renales durante la insuficiencia renal aguda y crónica. Este estudio tuvo por objetivo determinar los posibles efectos terapéuticos del tadalafil - un inhibidor específico de la PDE-5 - sobre la fibrosis renal inducida por una obstrucción ureteral unilateral (OUU). Métodos: Se utilizaron ratas machos Sprague-Dawley, divididas de manera aleatoria en tres grupos (n = 6): operación simulada, OUU y tratamiento con tadalafil (10 mg/72 horas, IG), y OUU (OUU+T). La obstrucción uretral unilateral fue inducida por una ligadura completa del uréter izquierdo y 14 días después de la cirugía, se observaron niveles de monofosfato de guanosina cíclico (GMP) urinario, alfa-actina de músculo liso (α-SMA), y factor de crecimiento transformante βeta (FCT-β), así como cambios histológicos en todos los animales. Resultados: La fibrosis renal inducida por obstrucción uretral unilateral fue confirmada por un aumento del nivel de α-SMA, deposición de colágeno, dilatación tubular, infiltración de células inflamatorias y necrosis. También se observó un aumento del nivel de FCT-β renal y una disminución del nivel de GMP urinario en los animales con obstrucción, además de una reducción del aclaramiento de la creatinina. El tratamiento con tadalafil, que restauró el nivel de GMP urinario de los animales, atenuó significativamente los cambios fibróticos y el aumento de FCT-β en los riñones. Conclusión: Este estudio sugiere que el tratamiento con tadalafil mejora la fibrosis renal al reducir la expresión de FCT-β y puede tener una importante relevancia clínica por cuanto el tadalafil se usa hoy día clínicamente para tratar la disfunción eréctil y la hipertensión pulmonar.

Role of scaffolding protein JLP on the progression of renal interstitial fibrosis in mice model of unilateral ureteral obstruction and its underlying mechanism / 中华肾脏病杂志

Objective To observe the effect of JLP deficiency on the progression of renal interstitial fibrosis in mice model of unilateral ureteral obstruction (UUO),and to investigate the role and underlying mechanism of JLP in the development of renal fibrosis in obstructive nephropathy.Methods jlp Wild type (jlp+/+) and jlp deficient (jlp-/-) mice were divided into four groups:jlp+/+-and jlp-/--sham-operated groups(jlp-/--sham group and jlp+/+-sham group),jlp+/+-and jlp-/--unilateral ureteral obstruction (UUO)-operated groups (jlp/--UUO group and jlp+/+-UUO group).Mice were sacrificed at 7 days and 14 days after the operation respectively to evaluate the fibrosis by Masson staining.The expression of JLP in jlp +/+ renal tissue was assayed by immunohistochemistry staining,immunofluorescence and Western blotting.Immunohistochemical staining was used to detect the expression of α-smooth muscle actin (α-SMA),collagen Ⅰ (COL-Ⅰ),collagen Ⅲ (COL-Ⅲ) and transforming growth factor-β1 (TGF-β1) in sham and UUO groups.Besides,the α-SMA,COL-Ⅰ,COL-Ⅲ,TGF-β1,p-Smad2 and p-Smad3 protein levels were also analyzed by Western blotting in four groups.Results The expression of JLP was mainly demonstrated in the renal tubules of mice.A large amount of collagen deposition was observed in the renal interstitial area in jlp-/--UUO group compared to jlp+/+-UUO group.Similarly,the expression of α-SMA,COL-Ⅰ,COL-Ⅲ and TGF-β1 was significantly increased in the kidney cortices in jlp-/--UUO-operated groups.Meanwhile,Western blotting showed that the expression of α-SMA,COL-Ⅰ,COL-Ⅲ,and TGF-β1 protein was obviously higher in jlp-/--UUO group.Moreover,the expression of p-Smad2 and p-Smad3 protein was markedly higher in jlp-/--UUO group.Conclusion Scaffolding protein JLP is critical in preventing renal fibrosis through the inhibition of TGF-β1 expression and myo-fibroblast production.

Comparison of growth and apoptosis of fibroblasts derived from kidneys with and without interstitial fibnwis / 中华肾脏病杂志

Objective To study the role of fibroblasts in the pathomechanisms of renal interstitial fibrosis(RIF). Methods Growth behavior and apoptos, of renal interstitial fibroblasts in cultures, established using renal biopsies of casts with and without RIF, were studied. Results There were significant alterations in the growth behavior, the differentiation pattern of potentially mitotic fibroblast populations and programmed cell death in cultures derived from kidneys with RIF, as compared with cultures of normal origin. Conclusion The abnormal growth and apoptosis of fibroblasts may play an im-portant role in RIF. Inhibiting the proliferation and promoting the programmed death of fibroblasts may be benificial to patients with RIF.