Peroxisome Proliferator-activated Receptor-γ Agonist Pioglitazone Fails to Attenuate Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

Renal tubulointerstitial fibrosis is the common ending of progressive renal disease. It is worth developing new ways to stop the progress of renal fibrosis. Peroxisome proliferator-activated receptor-γ（PPARγ） agonists have been studied to treat diabetic nephropathy, cisplatin-induced acute renal injury, ischemia reperfusion injury and adriamycin nephropathy. In this study, unilateral ureteral obstruction（UUO） was used to establish a different renal fibrosis model. PPARγ agonist pioglitazone was administrated by oral gavage and saline was used as control. At 7th and 14 th day after the operation, mice were sacrificed for fibrosis test and T lymphocytes subsets test. Unexpectedly, through MASSON staining, immunohistochemistry for α-SMA, and Western blotting for α-SMA and PDGFR-β, we found that pioglitazone failed to attenuate renal fibrosis in UUO mice. However, flow cytometry showed that pioglitazone down-regulated Th1 cells, and up-regulated Th2 cells, Th17 cells and Treg cells. But the Th17/Treg ratio had no significant change by pioglitazone. Real-time PCR results showed that TGF-β and MCP-1 had no significant changes, at the same time, CD4＋ T cells associated cytokines were partially regulated by pioglitazone pretreatment. Taken together, pioglitazone failed to suppress renal fibrosis progression caused by UUO.

Ginsenoside Rb1,a Panoxadiol Saponin against Oxidative Damage and Renal Interstitial Fibrosis in Rats with Unilateral Ureteral Obstruction

Objective:To investigate the possible protective effect and mechanism of ginsenoside Rb1 against oxidative damage and renal interstitial fibrosis on rats with unilateral ureteral obstruction(UUO). Methods:In total,80 male rats were randomly divided into 4 groups,20 in each group:the sham operated group (SOR),UUO group,UUO with ginsenoside Rb1 treatment group(treated with intraperitoneal injection of 50 mg/ kg daily) and UUO with Losartan treatment group(as the positive control,treated with 20 mg/kg by gastr...

Arterially transplanted mesenchymal stem cells in a mouse reversible unilateral ureteral obstruction model： in vivo bioluminescence imaging and effects on renal fibrosis

Background Chronic kidney disease （CDK） is a worldwide health problem, but there is currently no effective treatment that can completely cure this disease. Recently, studies with mesenchymal stem cells （MSCs） on treating various renal diseases have shown breakthroughs. This study is to observe the homing features of MSCs transplanted via kidney artery and effects on renal fibrosis in a reversible unilateral ureteral obstruction （R-UUO） model. Methods Thirty-six Balb/c mice were divided into UUO group, UUO-MSC group, and sham group randomly, with 12 mice in each group. The MSCs had been infected by a lentiviral vector to express stably the luciferase reporter gene and green fluorescence protein genes （Luc-GFP-MSC）. Homing of MSCs was tracked using in vivo imaging system （IVIS） 1, 3, 14, and 28 days after transplantation. Imaging results were verified by detecting GFP expression in frozen section under a fluorescence microscope. E-cadherin, α-SMA, TGF-β1, and TNF-α mRNA expression in all groups at 1 and 4 weeks after transplantation were analyzed by quantitative PCR. Results Transplanted Luc-GFP-MSCs showed increased Luciferase expression 3 days after transplantation. The expression decreased from 7 days, weakened thereafter and could not be detected 14 days after transplantation. Quantitative PCR results showed that all gene expressions in UUO group and UUO-MSC group at 1 week had no statistical difference, while at 4 weeks, except TGF-β expression （P〉0.05）, the expression of E-cadherin, α-SMA, and TNF-α in the above two groups have statistical difference （P〈0.01）. Conclusion IVIS enables fast, noninvasive, and intuitive tracking of MSC homing in vivo. MSCs can be taken home to kidney tissues of the diseased side in R-UUO model, and renal interstitial fibrosis can be improved as well.

Trabecular bone deterioration at the greater trochanter ol mice with unilateral obstructive nephropathy

Our previous study showed the early molecular responses of bone in response to obstructive nephropathy in a unilateral ureteral obstruction （UUO） mouse model. Here, we addressed the changes in trabecular bone properties at greater trochanter, the proximal and the distal metaphysis of femur in UUO mice. The male mice were subjected to UUO （n= 10） or sham operation （n= 10）. All mice were killed on day 7 after the surgical operation. The micro-computed tomography （micro-CT） analysis for different femoral trabecular bone sites demonstrated pathological alterations of trabecular bone mass and micro-networks at greater trochanter as shown by decreases in bone mineral density/bone volume （P〈O.05） and trabecular number （P〈O.05） and increases in trabecular separation （P〈O.01） and bone surface/bone volume （P〈O.05） in UUO mice. The present study demonstrates that UUO-induced unilateral obstructivenephropathy has markedly detrimental effects on the trabecular trochanter of the femur.

CTRP1 Attenuates UUO-induced Renal Fibrosis via AMPK/NOX4 Pathway in Mice

Clq/TNF-related protein 1(CTRP1),a conserved protein of the Clq family,plays a key role in cardiovascular and metabolic diseases.However,the role of CTRP1 in renal injury is unclear.The purpose of this study is to explore the role of CTRP1 in unilateral ureteral obstruction(UUO)-induced renal fibrosis and to elucidate the underlying mechanism.Using gene delivery system,CTRP1 was overexpressed in the kidney,then the mice were operated to induce UUO model after adenovirus transfection.It was found that the expression of CTRP1 in the renal tissue was decreased in mice after UUO.CTRP1 overexpression decreased the kidney function and kidney weight index.Moreover,CTRP1 reduced oxidative stress and renal collagen deposition in vivo.As expected,we found that CTRP1 activated AMP-activated kinase(AMPK)and decreased NOX4 expression,while silencing AMPKal abolished the protective effects of CTRP1 overexpression in mice after UUO.In conclusion,CTRP1 may protect against UUO-induced renal injury via AMPK/NOX4 signaling.Our results indicate that CTRP1 exhibits potential effects to treat renal fibrosis caused by UUO.

Role of Protease Activated Receptor-2 Expression in Renal Interstitial Fibrosis Model in Mice

Summary： The role of protease activated receptor-2 （PAR-2） in the renal tubulointerstitial lesion induced by unilateral ureteral obstruction （UUO） was explored. Mice were sacrificed on the day 1, 3, 5, 7, 10, 14 and 21 after UUO. The expression of PAR-2 mRNA and protein and a-smooth muscle actin （α-SMA） protein in tubuloin,terstitium was detected by RT-PCR and immunohistochemistry at each time point, respedtively. The results showed that the PAR-2 expression in renal tubulointerstitium was increased progressively starting from 24 h to the day 14 post-ligation, and it was significantly associated with the relative volume of interstitium and the positive area of α-SMA. PAR-2 was mainly expressed in renal tubule epithelial cells, especially in proximal tubular cells. It also located in renal capillary ansa, interstitial infiltrate cells and fibroblasts. It was concluded that PAR-2 was active in interstitial and tubular cells in the early phase of fibrotic process and played an important role in mediating the tubulointerstitial lesion after UUO.

MHC class Ⅱ in renal tubules plays an essential role in renal fibrosis

Immunomodulation has been considered a potential therapeutic approach for chronic kidney disease(CKD).Although it has been previously reported that CD4+T cells contribute to the development of renal fibrosis after UUO,the role of MHC class Ⅱ(MHCII)in UUO-induced renal fibrosis remains largely uncharacterized.The present study reports that the expressions of MHCII molecules in renal cortical tubules are upregulated in a mouse unilateral ureter obstruction(UUO)model.Global or renal tubule-specific ablation of MHCII significantly alleviates renal fibrosis following UUO.Additionally,renal expression of profibrotic genes showcased consistent reduction in both MHCII gene deficient mouse lines.These results demonstrate that renal tubular MHCII plays an important role in pathogenesis of renal fibrosis.