3-nitrotyrosine and Ureteral-Obstruction

Maternal undernutrition is known to reduce glomerular number but it may also affect tubulointerstitium, capillary density, and response to oxidative stress. To investigate whether the latter elements are affected, we examined the response to unilateral ureteral obstruction (UUO), an established model of renal tubulointerstitial fibrosis, in the kidney of offspring from control and nutrient restricted rats. Six-week old male offspring from rats given food ad libitum (CON) and those subjected to 50% food restriction throughout pregnancy (NR) were subjected to UUO for 7 days. Body weight was significantly lower in NR. Systolic blood pressure and blood urea nitrogen increased similarly in CON and NR after UUO. Tubular necrosis in the obstructed kidney, on the other hand, was more extensive in NR. Also, the collagen area, a marker of fibrosis, of the obstructed kidney was significantly increased compared with the contralateral kidney only in NR. Capillary density was decreased similarly in the obstructed kidney of CON and NR compared with the contralateral kidney. Urine nitrate/nitrite, a marker of nitric oxide production, from the obstructed kidney was significantly increased in NR compared with CON. Nitrotyrosine, a marker of nitric oxide-mediated free radical injury, was increased in the obstructed kidney compared with the contralateral kidney in both CON and NR, but the extent was significantly greater in NR. In conclusion, more severe tubular necrosis and fibrosis after UUO was observed in NR, which was thought to be due to increased nitrosative stress.

Topics: Animals; Disease Models, Animal; Female; Fibrosis; Kidney; Kidney Tubular Necrosis, Acute; Male; Malnutrition; Maternal-Fetal Exchange; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrites; Oxidative Stress; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Tyrosine; Ureteral Obstruction

Beraprost sodium (BPS), as a prostacyclin analog, plays a significant role in various diseases based on its antiplatelet and vasodilation functions. However, its regulation and role in chronic kidney disease (CKD) still remain elusive. Here, we determined whether BPS could alleviate renal interstitial fibrosis, and improve the renal function and its therapeutic mechanism. In vitro, BPS increased angiogenesis in the HUVECs incubated with BPS detected by tube formation assay and repair damaged endothelial cell-cell junctions induced by hypoxia. In vivo, mice were randomly assigned to a sham-operation group (sham), a unilateral ureteral obstruction group (UUO), and a BPS intragastrical administration group (BPS), and sacrificed at days 3 and 7 post-surgery (six in each group). In UUO model, tissue hypoxia, renal inflammation, oxidative stress, and fibrotic lesions were detected by q-PCR and Western blot techniques and peritubular capillaries (PTCs) injury was detected by a novel technique of fluorescent microangiography (FMA) and analyzed by MATLAB software. Meanwhile, we identified cells undergoing endothelial cell-to-myofibroblast transition by the coexpression of endothelial cell (CD31) and myofibroblast (a-SMA) markers in the obstructed kidney. In contrast, BPS protected against interstitial fibrosis and substantially reduced the number of endothelial cell-to-myofibroblast transition cells. In conclusion, our data indicate the potent therapeutic of BPS in mitigating fibrosis through repairing renal microvessels and suppressing endothelial-mesenchymal transition (EndMT) progression after inhibiting inflammatory and oxidative stress effects. KEY MESSAGES: BPS could improve renal recovery through anti-inflammatory and anti-oxidative pathways. BPS could mitigate fibrosis through repairing renal microvessels and suppressing endothelial-mesenchymal transition (EndMT).

Topics: Adult; Animals; Chemokine CCL2; Disease Models, Animal; Epoprostenol; Fibrosis; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Kidney; Kidney Function Tests; Male; Mice, Inbred C57BL; Microvessels; Neovascularization, Physiologic; Regeneration; Transforming Growth Factor beta; Tyrosine; Uncoupling Protein 2; Ureteral Obstruction; Vascular Endothelial Growth Factor A

To investigate the roles of nitric oxide (NO) and NO synthases [endothelial constitutive NO synthase (eNOS) and inducible NO synthase (iNOS)] in the pathogenesis of ureteric damage during the course of obstructive uropathy.. The expression of nitrotyrosine, eNOS and iNOS was studied in 54 Sprague-Dawley rats using immunohistochemistry with concurrent immunohistochemical staining.. Hypertrophy and fibrotic changes of the smooth muscle of the obstructed ureters were noticed after ureteric ligation. The expression of iNOS, eNOS and nitrotyrosine in the smooth muscle layer was noticed from Days 7, 10 and 14 after ligation, respectively, increased until Day 21 post-ligation and then decreased. The expression of nitrotyrosine in the smooth muscle layer was significantly correlated with the expression of iNOS and eNOS (r=0.9698 and 0.9683, respectively; p<0.0001 for both).. NO and NO synthases may play important roles in tissue damage of the smooth muscle layer in obstructed ureters.

Topics: Animals; Female; Muscle, Smooth; Nitric Oxide; Rats; Rats, Sprague-Dawley; Time Factors; Tyrosine; Ureteral Obstruction