| Background and objective Congenital hydronephrosis(CHN)is one of the most common developmental malformations found by prenatal ultrasound,with an incidence of 1-5%.There are many causes of congenital hydronephrosis,from transient hydronephrosis in the uterus to clinically significant congenital abnormalities of kidneys and urinary tract.The most common cause of hydronephrosis in the clinic is pelvic-ureteric junction obstruction(PUJO),the incidence rate is 0.1%,accounting for 50% of cases of severe hydronephrosis,which is the common cause of end-stage renal failure in infants and children.Due to the lack of understanding of the pathophysiological mechanism and outcome of CHN,there is controversy about the treatment and follow-up management of children with hydronephrosis caused by congenital PUJO.Since CHN occurs in the embryonic stage,morphological and hemodynamic changes of the fetal kidney during development can only be monitored by imaging.Under pathological conditions,renal function changes may appear earlier than morphological changes,and the status of fetal renal function is closely related to the outcome of CHN and the choice of future treatment options.The exploration of related pathophysiological changes during the embryonic period is helpful for perinatal and pediatricians to better understand the normal development of fetal kidneys and to develop more reasonable treatment options for children with CHN.However,it is difficult to collect fetal kidney specimens in clinical practice.At present,the research on function related to normal and pathological conditions in fetal development is almost blank.Therefore,how to predict or detect the renal function changes of CHN fetus is an urgent problem to be solved.Urine concentration and water reabsorption dysfunction are early functional changes in the kidney of hydronephrosis.It is reported that the downregulation of aquaporin1-3(AQP1-3)is associated with these changes.AQP1 is the earliest discovered aquaporin protein,which is abundant in the renal cortex and is mainly present at the apical and basolateral plasma membranes of the proximal tubule and descending thin limb of the loop of Henle,which plays an important role in the water reabsorption of the proximal nephron and the concentration of urine.AQP2 is mainly located in the apical plasma membrane and cytoplasm of the principal cells of the renal collecting duct,and is essential for water reabsorption in the collecting duct.The physiological process of AVP regulating renal reabsorption of water is mainly through AQP2;AQP3 is expressed in the basolateral plasma membrane of principal cells of inner medullary collecting ducts,it also plays a role in the reabsorption of water and the production of concentrated urine.Previous studies in children with hydronephrosis showed that the expression of AQP1-3 was down-regulated in hydronephrosis,and the down-regulated AQP1-3 was the main cause of impaired renal water reabsorption and urine concentration.The long-term dilution of urine is prone to electrolyte imbalance,thus,the normal expression of kidney AQPs is very important for the maintenance of the body's water metabolism balance.However,due to the particularity of fetal development in the uterus,it is not clinically possible to directly detect the expression of AQPs in the fetal kidney.Therefore,the previous studies on the expression of AQPs in fetal kidneys have hardly been reported.AQP2 is mainly located in the renal collecting duct epithelial cells in human.Previous studies have found that about 3% of kidney AQP2 can be excreted in the urine with the epithelial cells of the detached collecting duct,and the proportion of AQP2 excreted in the urine is not affected by the physiological state of the human body.This suggests that AQP2 in urine can reflect the expression level of AQP2 protein in the kidney.Among children with CHN,some researchers found that the level of AQP2 in their urine was positively correlated with the severity of hydronephrosis and urine concentration capacity,which indicates that AQP2 in the urine of children with CHN can indirectly reflect the severity of hydronephrosis and the concentration function.However,it is difficult to collect fetal urine directly during he fetal period.The fetal urine is the main source of amniotic fluid in the middle and late pregnancy period,unlike other subtypes of AQP,AQP2 is mainly located in the human kidney collecting duct principal cells,which have kidney tissue specificity.Therefore,if the AQP2 protein can be detected in amniotic fluid,it should be derived from the fetal kidney.However,whether AQP2 protein can be detected in amniotic fluid and its relationship with AQP2 in fetal kidney is blank.Amniocentesis is an invasive examination,but with the implementation of the family planning second child policy,more and more elderly women need amniocentesis for prenatal screening,which provides the possibility to detect AQP2 through amniocente.Therefore,the first and second parts of this study explored the expression of AQP1-3 in normal and hydronephrosis fetal kidneys and the relationship of AQP2 between amniotic fluid and fetal kidneys.At present,there are still controversies in the treatment and management of CHN patients.The principle of treatment is as follows: for patients with mild CHN,conservative observation should be the choice,but for patients with moderate to severe CHN caused by PUJO often require surgical removal of obstruction.However,many clinical and animal studies have found that the urine concentration capacity cannot be completely restored even after the release of the obstruction,and there will still be a continuous large amount of diluted urine,which is related to the abnormal expression of renal AQP proteins.Because the long-term dilution of urine is easy to cause electrolyte imbalance in the body,many scholars have done many work to explore methods to protect renal concentrating function after release of the obstruction.Up to now,there are still no ideal methods to prevent the downregulation of AQPs in CHN infants.The statins and sartans can prevent the down-regulation of AQPs caused by obstruction,and promote the recovery of AQPs protein expression and renal urinary concentration ability,but these drugs may aggravate the kidney damage of infants and young children caused by obstruction,which limits their clinical application.In recent years,reports of the protective effects of erythropoietin(EPO)on impaired kidney function have attracted schlors' attention.Ren Chuan et al found that EPO can promote the recovery of AQP2 protein esspression and renal function after elease of ureteral obstruction in young rats.However,the specific mechanism of how EPO regulates AQP2,and whether it can promote the expression of AQP1 and AQP3 proteins and the recovery of renal water reabsorption after release of bilateral ureteral obstruction have not been reported yet.At present,EPO has been used clinically to treat neonatal hypoxic ischemic encephalopathy.Whether EPO can be used in children with CHN to protect renal function requires further study.In order to better understand the pathological and physiological changes and outcomes of CHN at the molecular level and to explore possible treatment methods,it is necessary to perform animal experiments.Rat ureteral obstruction model has been widely used for the study of obstructive nephropathy and renal fibrosis.Most children with clinical CHN are partially obstructed,but the degree of partial obstruction in animal models is not easily controlled and quantified.In the complete ureteral obstruction model,the degree of obstruction is easier to control and quantify,and is often used to study the pathophysiological changes of the kidney caused by obstruction.Therefore,the third part of this study used the rat model of complete ureteral obstruction to verify the pathophysiological changes of the kidney caused by complete ureteral obstruction and the protective effect of EPO on AQP1-3 protein and kidney function in rat kidney after release of ureteralobstruction.Among the subtypes of AQPs expressed in the kidney,AQP2 is the most closely related to urine concentration,and is associated with a variety of kidney urine concentrating and diluting dysfunction diseases.Previous study also found that EPO can promote the recovery of AQP2 expression in rat kidney after the obstruction is relieved,but there are many influencing factors in vivo.The mechanism of EPO on the direct regulation of AQP2 in renal collecting duct cells and the mechanism are still unclear.In vitro studies can rule out the interference of other factors in the body.If EPO can directly up-regulate the expression of AQP2 in vitro,it may provide a therapeutic basis for the treatment of AQP2-related diseases including congenital hydronephrosis.Therefore,the fourth part of this study used the m IMCD-3 cell line to verify the effects and mechanisms of EPO on AQP2 expression in collecting duct cells.In summary,this study mainly elucidated the expression of renal aquaporin in the kidney of congenital hydronephrosis and the regulation mechanism of EPO,and clinically detected the normal and abnormal expression of aquaporin in the kidney during embryonic period.Animal model were made and in vitro experiments were performed to confirm the protective mechanism of EPO on the expression of renal AQP1-3 protein and renal function in young rat with ureteral obstruction.The main research purposes and contents are as follows:(1)To observe the expression of AQP1-3 m RNA and protein in normal and hydronephrosis human fetal kidney during development.(2)To explore the relationship between AQP2 detected in amniotic fluid and AQP2 protein expression in fetal kidney.(3)To investigate the effect of EPO on AQP1-3 protein expression and renal function in rat kidney after release of ureteral obstruction and explore the mechanism.(4)To explore the effect of EPO on the expression of AQP2 in m IMCD-3 cells and the mechanism.Part ? Expression of AQP1-3 in normal and hydronephrotic human fetal kidneyMaterials and Methods 1.A total of 22 normal fetal kidneys were collected(8 cases of 16-21 W,8 cases of 23-28 W,6 cases of 30-36W).2.A total of 7 hydronephrotic fetal kidneys were collected(4 cases of 32 W,3 cases of 34 W,the hydronephrosis were all unilateral).3.Positive controls: 8 cases of normal adult kidney tissue(6 males,2 females,aged(56±4.3 years old)were from normal renal tissues adjacent to renal pelvic cancer confirmed by pathological examination after renal resection.4.The morphological changes of fetal kidney were detected by HE staining technique.The localization and expression of AQP1-3 protein in all kidney issues were detected by immunohistochemistry.The expression of AQP1-3 m RNA in all kidney tissues was detected by Real-time PCR.Detection of AQP1-3 protein expression in all kidney tissues by Western blot 5.Statistical Analysis: Statistical analysis was performed using SPSS 21.0 statistical software,and the measurement data were expressed as mean ± standard deviation(x ±s).An independent sample t test was used to compare the differences between two groups,and one-way ANOVA was used to compare the the differences among three groups or more.With ? = 0.05 as the test level,P < 0.05 was considered statistically significant.Results 1.The results of HE staining showed that there were fewer fetal cortical parts in the earlier middle stages of pregnancy,and the number of glomeruli in the cortex was smaller and volume of which was larger.As the gestational age increased,the renal cortex gradually developed,and the number of glomeruli in the cortex also increased gradually.In the earlier middle stages of pregnancy,the renal medulla contains more renal interstitial tissues,and the renal tubules are scarce.As the gestational age increases,the nephron gradually develops,and the renal tubules and capillary networks in the medulla gradually increase.2.The results of immunohistochemistry showed that the expression of AQP1-3 protein in fetal kidney was consistent with that of adult.AQP1 was mainly located in the the apical and basolateral plasma membranes of the proximal tubule and descending thin limb of the loop of Henle,and also expressed in glomerular capillary endothelial cells.AQP2 was mainly located in the apical plasma membrane of the principal cell of the collecting duct.AQP3 is mainly located in the basolateral membrane of the collecting duct.With the increase of gestational age,the number of renal tubules positively expressing AQP1-3 gradually increased,and the expression intensity increased gradually.However,the expression intensity of AQP1-3 was still weaker than that of adult kidney tissue even in the late pregnancy.The positive expression of AQP1-3 protein in the fetal kidney of the hydronephrosis group in the third trimester was weaker han that of the fetal kidney of the same pregnancy.3.RT-PCR results showed that with the increase of gestational age,the AQP1-3 m RNA gradually increased in renal tissues,the expression of AQP1-3 m RNA in fetal kidney tissues of 15-21 W group,23-28 W group and 30-36 W group were as follows: AQP1:(13.4 ± 7.3)% Vs.(31.7 ± 5.7)% Vs.(71.1 ± 1.9)%;AQP2:(12.0 ± 2.3)% Vs.(32.2 ± 4.3)% Vs.(71.1±1.9)%;AQP3:(16.1±6.3)%Vs.(47.2±6.3)% Vs.(81.5±3.1)%;P < 0.05.The results of RT-PCR showed that the expression of AQP1-3 m RNA in the fetal kidney of the hydronephrosis in the third trimester was lower than that in the normal fetal kidney group,AQP1:(38.3±7.5)%Vs.(70.8±6.2)%;AQP2:(41.2± 6.3)% Vs.(76.9 ± 4.3)%;AQP3:(63.6 ± 8.7)% Vs.(81.1 ± 4.6)%;P < 0.05.4.Western blot results showed that with the increase of gestational age,the AQP1-3 protein gradually increased in renal tissues,the expression of AQP1-3 protein in fetal kidney tissues of 15-21 W group,23-28 W group and 30-36 W group were as follows: AQP1: 0.228±0.10 Vs.0.304±0.091 Vs.0.543±0.095;AQP2:0.157±0.086 Vs.0.269±0.079 Vs.0.441±0.011;AQP3: 0.152±0.047 Vs.0.261±0.086 Vs.0.512 ±0.089;P<0.05.Western blot results showed that the expression of AQP1-3 protein in fetal kidneys of patients with hydronephrosis was lower than that of normal fetal kidney group,AQP1:0.281±0.039 VS.0.449±0.039;AQP2: 0.306±0.112 Vs.0.567±0.142;AQP3:0.261 ± 0.086 VS.0.512 ± 0.089;P<0.05.Part ? The relationship between AQP2 in amniotic fluids and AQP2 protein in fetal kidneyMaterials and Methods 1.A total of 22 cases normal fetal kidney specimens were collected(8 cases of 16-21 W,8 cases of 24-30 W,6 cases of 32-38W).24 cases of amniotic fluid were collected(7 cases of 16-21 W,6 cases of 24-30 W,8 cases of 32-38W).The morning urine of 10 healthy adult women(26.0±2.3)years old was collected as positive control.2.Westernblot was used to detect the expression of AQP2 protein in fetal kidney.The AQP2 in amniotic fluid was detected by enzyme-linked immunosorbent assay(ELISA).The osmotic pressure of amniotic fluid of different pregnancy period was detected by freezing point osmometry.The sodium,potassium and creatinine and urea nitrogen concentration of the amniotic fluid was detected by automatic biochemical detector.3.Statistical Analysis:Statistical analysis was performed using SPSS21.0 software.The measurement data were expressed as mean±standard deviation(x ±s);the normality test was performed by K-S test,and the comparison among groups was analyzed by one-way ANOVA.The LSD-t test was used to test the relationship between AQP2 in amniotic fluid and that in fetal kidney by Pearson correlation analysis.The test was performed with ?=0.05,P<0.05 was considered statistically significant.Results 1.Western blot analysis showed that the expression levels of AQP2 protein in fetal kidneys of 16-21 W,24-30 W and 32-38 W were 0.982±0.325 Vs.1.556±0.262 VS.2.06±0.228.The difference among groups was statistically significant(F=19.646,P < 0.05).2.ELISA results showed that the concentrations of AQP2 detected in the amniotic fluid of 16-21 W group,24-30 W group and 32-38 W group and adult urine were(30.243±5.812)mg/L Vs.(35.112±7.265)mg/L Vs.42.575±1.226)mg/L Vs.(46.513±0.449)mg/L.The difference among the groups of was statistically significant(F=14.402,P<0.05).3.The level of AQP2 in amniotic fluid of different pregnancy was positively correlated with the expression of AQP2 protein in fetal kidneys(r=0.872,P=0.000).Part ? Effects of EPO on renal function and renal AQP1-3 protein expression after bilateral ureteral obstruction in yong ratsMaterials and Methods 1.Experimental protocol 1)Twenty male SD rats,weighing(160±10)g,were randomly divided into BUO group and sham group,and n=10 in each group.2)Thirty male SD rats,weighing(160±10)g,were randomly divided into BUO-3R group,BUO-3R+EPO group and sham-3R group,n=10 in each group.3)Thirty male SD rats,weighing(160±10)g,were randomly divided into BUO-7R group,BUO-7R+EPO group and sham-7R group,each group n=10.2.Animal Model Preparation of BUO rats: After the rats were completely anesthetized,the both ureters were exposed and separated the ureter with a length of about 1 cm across the iliac vessels.The 0.5 cm long intravenous infusion needle with lateral opening is placed over the separated ureter and the cannula is ligated with a wire.BUO-R rats were anesthetized again 24 hours after obstruction,and the silk and cannula ligated to both ureters were removed.Rats in sham group were subjected to sham operations identical to the ones used for BUO rats without occlusion of both ureters.3.Drug intervention: rats in the BUO-3R+EPO group were given intraperitoneal injection of EPO on the 1st and 3rd after the release of the obstruction and immediately after the release of the obstruction;the rats in the BUO-7R+EPO group were given intraperitoneal injection of EPO on the 1st,3rd,5th and 7th day after the release of the obstruction and immediately after the release of the obstruction,the BUO-3R,Sham-3R,BUO-7R and Sham-7R groups were intraperitoneally injected with an equal volume of saline at the same time point.4.Specimen Collection: The rats in the BUO group were sacrificed 24 hours after the obstruction;the spicemen of the BUO-3R,BUO-3R+EPO and Sham-3R groups were taken on the 3rd day after the obstruction was relieved.The spicemen of BUO-7R,BUO-7R+EPO and Sham-7R groups were taken on the 7th day after the obstruction was relieved.Blood was collected from the inferior ena cava for renal function test,the kidneys on both sides were taken.Ten rats at each time point were sacrificed,five rat kidneys were used for subsequent Western blot test of AQP1-3,?-SMA and TGF-? protein;the other five rat kidneys were used for HE staining,Masson staining and immunohistochemistry test of AQP1-3 and ?-SMA and TGF-?.5.Statistical analysis: SPSS21.0 statistical software was used for data analysis.Measurement data were expressed as mean ± standard deviation(x ±s).Comparison between the two groups was performed by independent sample t test,and comparison among three groups and more was performed with One-way analysis of variance.With ? = 0.05 as the test level,P < 0.05 was considered statistically significant.Results 1.After 24 hours of bilateral ureteral obstruction,the renal function in the BUO group and the sham group were as follow: urea nitrogen: 117.9±3.0 mmol/L Vs.6.9±0.2 mmol/L,respectively,P<0.05;the creatinine concentration: 230±14.7?mol/L Vs.54.3±1.1?mol/L,respectively,P<0.05;plasma osmotic pressure: 338.8±3.2 mosmol/kg H2 O Vs.293.7±5.2 mosmol/kg H2 O,P<0.05;The serum potassium concentration: 6.5±0.3 mmol/L Vs.4.4±0.2 mmol/L,P<0.05.Rats within 1w after release of the obstruction had significant polyuria and low urine osmotic pressure.2.Renal function test results showed that on the 3rd day after release of the obstruction,the results of renal function test in BUO-3R+EPO group,BUO-3R group and Sham-3R group were as follows:(urea nitrogen: 21.9±1.1 mmol/L Vs.27.1±2.1 mmol/L Vs.6.8±0.3mmol/L,P<0.05;serum creatinine concentration was 113.4±3.3?mol/L Vs.134.2±5.4?mol/L Vs.54.1±1.4?mol/L,P<0.05;The renal function test results of BUO-7R+EPO group,BUO-7R group and Sham-7R group were as follows: urea nitrogen 19.8±1.0 mmol/L Vs.22.9±0.8 mmol/L Vs.6.8±0.2mmol/L,P <0.05;the serum creatinine were 67.7±3.2?mol/L Vs.74.1±3.1 ?mol/L Vs.54.2±0.7 ?mol/L,respectively,P <0.05.3.The results of immunohistochemistry showed that AQP1 was mainly located in he the apical and basolateral plasma membranes of the proximal tubule and descending thin limb of the loop of Henle,and AQP2 was mainly located in the apical plasma membrane of the principal cells of the renal collecting duct;AQP3 was mainly located in the basolateral membrane of the renal collecting duct.On the 3rd day after release of the obstruction,the protein staining of AQP1-3 was strongest in the Sham-3R group,followed by the BUO-3R+EPO group,and weakest in the BUO-3R group.On the 7th day after release of the obstruction,AQP1-3 protein staining was also strongest in the Sham-7R group,followed by the BUO-7R+EPO group,and the BUO-7R group was the weakest.The results of immunohistochemistry showed that the protein staining of TGF-? and ?-SMA was the strongest in the BUO-3R group,the BUO-3R+EPO group was the second,and the Sham-3R group was the weakest on the 3rd day after release of the obstruction.On the 7th day after release of the obstruction,the BUO-7R group was the strongest,the BUO-7R+EPO group was the second,and the Sham-3R group was the weakest.4.Masson staining results showed that in the 3d day after release of the obstruction,the collagen staining of the experimental rat kidney was strongest in the BUO-3R group,the BUO-3R+EPO group was the second,and the Sham-3R group was the weakest;on the 7th day after release of the obstruction,the collagen staining of the experimental rat kidney was the strongest in the BUO-7R group,the BUO-7R+EPO group was the second,and the Sham-7R group was the weakest.5.Western blot results showed that the expression levels of AQP1,AQP2 and AQP3,TGF-?1 and ?-SMA in the BUO-3R+EPO group,BUO-3R group and Sham-3R group were significantly increased on the 3rd day after the obstruction was relieved.AQP1:(60.1 ± 5.8)% Vs.(35.3 ± 6.3)% Vs.(100 ± 6.6)%;AQP2:(59 ± 7)% Vs.(32 ± 8)% Vs.(100 ± 9)%;AQP3:(62±6.7)% Vs.(48.5±2.2)% Vs.(100±5.9)%;TGF-?:(109.4±4.4)%Vs.(141.7±5.5)%Vs.(100±3.9)%;?-SMA:(118.6±5.6)% Vs.(132.4±4.2)% Vs.(100±3.1)%,(P < 0.05).Western blot analysis showed that the expression levels of AQP1,AQP2 and AQP3,TGF-?1 and ?-SMA in the BUO-7R+EPO group,BUO-7R group and Sham-7R group were 7 days after the obstruction was relieved were as follws,AQP1:(87.8±7.3)%Vs.(41.1±5.6)%Vs.(100±2.3)%;AQP2:(81.8±4)% Vs.(41.1±7)% Vs.(100±3)%;AQP3:(96.7±6.8)% Vs.(49.5±5.1)% Vs.(100±7.4)%;TGF-?1:(147.3±2.3)% Vs.(321.3±13.1)% Vs.(100±2.7)%;?-SMA:(158.2 ± 7.5)% Vs.(319.5 ± 8.2)% Vs.(100 ± 4.6)%,(P < 0.05).Part ? EPO up-regulates AQP2 expression in m IMCD-3 cells via PI3K/AKT signal pathwayMaterials and Methods 1.Production of m IMCD-3 cell line transfected with AQP2 gene.2.MIMCD-3 cells transfected with AQP2 were cultured and adjusted to a cell density of 3×10 6 /ml.2 ml of cell suspension was added to each well,and evenly spread in a 6-well plate.After the cells were attached to the wall,they were starved for 24 hours.Add new medium,0 IU/ml,5 IU/ml,10 IU/ml,20 IU/ml EPO were added mixted in DMEM medium according to the groups,each group included 5 replicates,and place the culture plate in the 37 °C culture incubator with 5% CO2.After 72 hours of culture,the effects of different concentrations of EPO on the expression of AQP2 protein were observed by immunofluorescence and Western blot.3.m IMCD-3 cells transfected with AQP2 were cultured,adjusted to a cell density of 3×10 6 /ml,and 2 ml of cell suspension was added to each well,and evenly spread in a 6-well plate.After the cells were attached,the cells were starved for 24 hours.Then,the new medium was added,and 10 IU/ml of EPO was added to the DMEM medium according to the group,and each group was treated with 5 replicates,and put the culture plate in the 37 °C culture incubator with 5% CO2.After 0',5',10',15',30',1h,2h,3h,4h and 5h incubation,protein exptraction and western blot was performed to detect the optimal time for EPO to activate PI3K/AKT pathway.4.m IMCD-3 cells transfected with AQP2 were cultured,adjusted to a cell density of 3×10 6 /ml,and 2 ml of cell suspension was added to each well,and evenly spread in a 6-well plate.After the cells were attached,the cells were starved for 24 hours,then add new medium,and they were divided into our groups according to different experimental treatments: blank control group,EPO group,EPO+LY294002 group and LY294002 group.Each group was treated with 5 replicates.The culture plate was placed in a 37 °C incubator with 5% CO2.After 30 min culture,the protein was extracted,and the activation of PI3K/AKT signaling pathway was detected by Western blot.5.Statistical Analysis: SPSS21.0 statistical software was used for data analysis.Measurement data were expressed as mean ± standard deviation(x ±s).Comparison between the two groups was performed by independent sample t test,and comparison among three or more groups was performed with One-way analysis of variance.With ? = 0.05 as the test level,P < 0.05 is considered statistically significant.Results 1.Immunofluorescence results showed that AQP2 protein was mainly located in the cytoplasm of m IMCD-3 cells,and AQP2 staining was the strongest when EPO concentration was 10 IU/ml,which were consistent with immunofluorescence.Western blot results also showed that AQP2 protein expression in m IMCD-3 cells at EPO concentration of 10 IU was the strongest.2.Western blot showed that the expression of P-AKT was highest after 30 min of EPO administration,and the expression of EPO+LY294002 was lower than that of EPO after 30 min,P < 0.05.Conclusions 1.During human development,AQP1-3 in fetal kidneys increases with gestational age,which may be related to the gradual maturity of fetal renal function and hydronephrosis will down-regulate the expression of AQP1-3 in the fetal kidney,which may affect the fetal kidney urine concentration function.2.The AQP2 protein concentration detected in amniotic fluid can reflect the expression level of AQP2 protein in fetal kidney to some extent.3.EPO can promote the recovery of renal function and AQP1-3 protein xpression through anti-fibrosis in rats after release of bilateral ureteral obstruction.4.EPO up-regulates AQP2 expression in m IMCD-3 cells via PI3K/AKT signaling pathway. |
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