ABSTRACT
Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, and α-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.
Subject(s)
Angiotensin II/administration & dosage , Fibrosis/metabolism , Kidney Diseases/metabolism , Kidney/metabolism , Monomeric GTP-Binding Proteins/metabolism , Angiotensin II/metabolism , Animals , Atorvastatin , Disease Models, Animal , Fibrosis/drug therapy , Fibrosis/physiopathology , Heptanoic Acids/administration & dosage , Humans , Kidney Diseases/drug therapy , Kidney Diseases/physiopathology , Mice , Monomeric GTP-Binding Proteins/antagonists & inhibitors , Pyrroles/administration & dosage , Receptor, Angiotensin, Type 1/metabolism , Signal Transduction/drug effects , Ureteral Obstruction/diet therapy , Ureteral Obstruction/metabolism , Ureteral Obstruction/physiopathologyABSTRACT
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.
Subject(s)
Apoptosis/drug effects , Curcuma/chemistry , Diet , NF-kappa B/metabolism , Ureteral Obstruction/diet therapy , Animals , Blood Urea Nitrogen , Caspase 8/genetics , Caspase 8/metabolism , Creatinine/blood , Disease Models, Animal , Electrophoresis, Agar Gel , Fibrillar Collagens/metabolism , Kidney Cortex/drug effects , Kidney Cortex/metabolism , Kidney Cortex/pathology , Kidney Tubules/drug effects , Kidney Tubules/metabolism , Kidney Tubules/pathology , Male , NF-kappa B/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Ureteral Obstruction/genetics , Ureteral Obstruction/metabolismABSTRACT
PURPOSE: Unilateral ureteral obstruction (UUO) results in a significant change in renal blood flow (RBF) and glomerular filtration rate (GFR) by 24 hours. The intake of L-arginine, a substrate of nitric oxide (NO) synthase (NOS), can augment NO production. NO can maintain renal function through its vasodilatory action. Therefore, we examined the effect of dietary arginine supplementation on renal function in UUO. MATERIALS AND METHODS: GFR and RBF were measured by inulin and para-aminohippurate clearance, respectively, in control rats and in rats 24 hours after UUO. Rats were given arginine with or without the concomitant administration of N-nitro-L-arginine methyl ester. Urinary nitrate/nitrite (NO2/NO3) was measured by the Griess reaction and urinary cyclic guanosine monophosphate was determined by enzyme-linked immunosorbent assay. The expression of renal inducible NOS was determined by immunohistochemistry. RESULTS: Urinary NO2/NO3 was significantly increased after 2 weeks of arginine, confirming increased NO production. In control rats GFR and RBF were not significantly different in untreated vs arginine treated groups. In contrast, arginine treatment significantly increased GFR in the obstructed kidney (0.06 +/- 0.01 to 0.14 +/- 0.02 ml per minute per 100 gm) and the contralateral kidney compared with control UUO. RBF was also significantly increased by arginine. The increases in renal function with arginine were blunted by a NOS inhibitor in obstructed and contralateral kidneys. Inducible NOS expression was increased in obstructed and contralateral kidneys. CONCLUSIONS: This study demonstrates that L-arginine supplementation can improve renal function in acute UUO. This finding suggests that NO system may be a future site of pharmacological intervention for UUO.
