PDF(4624 KB)
Study on neurogenic bladder-induced renal fibrosis based on AngⅡ/TGF-β1/Smads signaling pathway
Zheng Yan, Ma Yuan, Ren Xuejing, Niu Peiyuan, Yan Lei, Cao Huixia, Shao Fengmin
PDF(4624 KB)
Study on neurogenic bladder-induced renal fibrosis based on AngⅡ/TGF-β1/Smads signaling pathway
Objective To establish a rat model of neurogenic bladder and analyze the changes in kidney morphology and function and the expression of proteins in AngiotensinⅡ(AngⅡ)/transforming growth factor β1 (TGF-β1)/Smads pathway. Methods Sprague-Dawley rats were randomly divided into experimental group (spinal nerve amputation, n=36) and control group (sham operation, n=12). At 6, 12, and 24 weeks, the bladder compliance was measured by cystometry, the kidney morphology was detected by B-ultrasound, blood urea nitrogen (BUN) and serum creatinine (Scr) in blood samples were examined, the kidney pathological changes were detected by Masson and HE staining, the distribution of AngⅡ/TGF-β1/Smads pathway proteins was analyzed by immunohistochemisty, and the protein expressions in kidney were detected by Western blotting. Results Urodynamics showed that the basic bladder pressure in experimental group was higher than that in control group. B-ultrasound showed that compared with the control group, the diameter of the renal pelvis of the rats with nerve dissection gradually increased (P<0.05), and the hydronephrosis was gradually obvious. Compared with the control group, the BUN and Scr in experimental group gradually increased (both P<0.01). Masson and HE staining showed that compared with the control group, the collagen expression and renal tubulointerstitial scores in experimental group were gradually increased (both P<0.01). Immunohistochemisty showed that compared with the control group, in experimental group the expression of angiotensinⅡ receptor type 1 (AT1), TGF-β receptor 1(TGF-βR1), phosphorylated Smad2 gradually increased (all P<0.01), the pathway inhibitor Smad6 gradually decreased (P<0.01), and the distribution of each protein in kidney was consistent. Western blotting showed a corresponding expression trend with immunohistochemisty. Conclusions In neurogenic bladder caused by bilateral spinal nerve amputation, due to bladder dysfunction, increased bladder pressure induces hydronephrosis, destruction of the nephron structure, activation of AngⅡ/TGF-β1/Smads pathway, and renal fibrosis. This method is effective and has clinical similarities, laying a foundation for exploring neurogenic bladder treatment.
Kidney / Fibrosis / AngiotensinⅡ / Transforming growth factor beta1 / Smads / Signaling pathway {{custom_keyword}} /
| [1] |
Chronic kidney disease affects 25% to 50% of patients with spina bifida. Guidelines recommend kidney function surveillance in these patients but practice patterns are unknown. Variations in kidney function surveillance were assessed in patients with spina bifida based on the hypothesis that the treating clinic and spina bifida type would be associated with kidney function surveillance.A retrospective cohort study was conducted of U.S. patients in the National Spina Bifida Patient Registry from 2013 to 2018. Followup was anchored at the 2013 visit. Participants with either an outcome event within 2 years of followup or more than 2 years of followup without an outcome event were included. Primary outcome was kidney function surveillance, defined as at least 1 renal ultrasound and serum creatinine within 2 years of followup. Primary exposures were clinic and spina bifida type, which were analyzed with covariates including sociodemographic and clinical characteristics in logistic regression models for their association with the outcome. Sensitivity analyses were performed using different kidney function surveillance definitions.Of 8,351 patients 5,445 were included with a median followup of 3.0 years. Across 23 treating clinics kidney function surveillance rates averaged 62% (range 6% to 100%). In multivariable models kidney function surveillance was associated with treating clinic, younger patient age, functional lesion level, nonambulatory status and prior bladder augmentation. Treating clinic remained a significant predictor of kidney function surveillance in all sensitivity analyses.Within the National Spina Bifida Patient Registry wide variation exists in practice of kidney function surveillance across treating clinics despite adjustment for key patient characteristics.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [2] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [3] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [4] |
To investigate the feasibility of restoring bladder function and prevention of renal deterioration by neurorrhaphy in rats with neurogenic bladder (NB).
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [5] |
To investigate bladder function patterns following cystostomy and determine the best time window for cystometric evaluation of bladder function in conscious rats.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [6] |
To determine the acute tissue effects of endoscopic electrosurgery using different electrodes, smooth ball, smooth bar, vertically grooved bar, and horizontally fluted bar electrodes were applied to the epithelial surface of porcine bladders in vivo with electrosurgical cutting current supplied at 100, 150, and 200 W. A single pass was made on the surface of the tissue under endoscopic control with sorbitol irrigation using an excursion rate of 5 mm/sec. Each electrode was tested five times at each setting. The depths of electrosurgical vaporization and coagulation were measured by a pathologist blinded to the electrode and power setting. Depth of vaporization increased with the power setting of the generator and was greater with the non-smooth electrodes than the smooth electrodes. The depth of coagulation likewise was greater using the non-smooth electrodes but increased only minimally with increasing power settings. There were no differences in vaporization or coagulation depth between the small ball and smooth bar electrodes. The differences between the vertically grooved bar and horizontally fluted bar also were insignificant, except that in one-third of cases, the horizontally fluted bar created clefts undermining otherwise-undamaged areas of tissue. Non-smooth electrosurgical electrodes produce more vaporization and coagulation than smooth electrodes at a given power setting and therefore may be preferred for endoscopic applications. For use in tissues where precise control is required, the vertically grooved bar may be superior to the horizontally fluted bar because it provides similar vaporization and coagulation with a more uniform tissue effect.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [7] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [8] |
To characterize the patient profile, medication utilization, and healthcare encounters of patients with neurogenic bladder dysfunction related to incontinence.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [9] |
Neurogenic bladder dysfunction (NGB) has an impact on the quality of life, which made it an important research subject in preclinical studies. The present review investigates the effect of stem cell (SC) therapy on bladder functional recovery after the onset of spinal cord injury (SCI), multiple sclerosis (MS), Parkinson disease (PD), and stroke in rodent models.All experiments evaluated the regenerative potential of SC on the management of NGB in rodent models up to June 2019, were included. From 1,189 relevant publications, 20 studies met our inclusion criteria of which 15 were conducted on SCI, 2 on PD, 2 on stroke, and 1 on MS in the rodent models. We conducted a meta-analysis on SCI experiments and for other neurological diseases, detailed urodynamic findings were reported.The common SC sources used for therapeutical purposes were neural progenitor cells, bone marrow mesenchymal SCs, human amniotic fluid SCs, and human umbilical cord blood SCs. There was a significant improvement of micturition pressure in both contusion and transaction SCI models 4 and 8 weeks post-SC transplantation. Residual urine volume, micturition volume, and bladder capacity were improved 28 days after SC transplantation only in the transaction model of SCI. Nonvoiding contraction recovered only in 56 days post-cell transplantation in the contusion model.Partial bladder recovery has been evident after SC therapy in SCI models. Due to limitations in the number of studies in other neurological diseases, additional studies are necessary to confirm the detailed mechanism for bladder recovery.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [10] |
程茜, 王玉. 抑制Src激酶可减轻单侧输尿管梗阻小鼠肾间质纤维化[J]. 中华肾脏病杂志, 2017, 33(8): 609-615. DOI: 10.3760/cma.j.issn.1001-7097.2017.08.008.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [11] |
马园园, 刘成海, 陶艳艳. 肾纤维化动物模型特点与研究进展[J]. 中国实验动物学报, 2018, 26(3): 398-403. DOI: 10.3969/j.issn.1005-4847.2018.03.020.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [12] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [13] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [14] |
Overproduction of transforming growth factor-beta clearly underlies tissue fibrosis in numerous experimental and human diseases. Transforming growth factor-beta's powerful fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation, and enhanced integrin expression that facilitates matrix assembly. In animals, overexpression of transforming growth factor-beta by intravenous injection, transient gene transfer, or transgene insertion has shown that the kidney is highly susceptible to rapid fibrosis. The same seems true in human disease, where excessive transforming growth factor-beta has been demonstrated in glomerulonephritis, diabetic nephropathy, and hypertensive glomerular injury. A possible explanation for the kidney's particular susceptibility to fibrosis may be the recent discovery of biologically complex interactions between the renin-angiotensin system and transforming growth factor-beta. Alterations in glomerular hemodynamics can activate both the renin-angiotensin system and transforming growth factor-beta. Components of the renin-angiotensin system act to further stimulate production of transforming growth factor-beta and plasminogen activator inhibitor leading to rapid matrix accumulation. In volume depletion, transforming growth factor-beta is released from juxtaglomerular cells and may act synergistically with angiotensin II to accentuate vasoconstriction and acute renal failure. Interaction of the renin-angiotensin system and transforming growth factor-beta has important clinical implications. The protective effect of inhibition of the renin-angiotensin system in experimental and human kidney diseases correlates closely with the suppression of transforming growth factor-beta production. This suggests that transforming growth factor-beta, in addition to blood pressure, should be a therapeutic target. Higher doses or different combinations of drugs that block the renin-angiotensin system or entirely new drug strategies may be needed to achieve a greater antifibrotic effect.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [15] |
To determine whether transforming growth factor beta (TGF-beta) could activate hyperplasia, hypertrophy, and altered collagen expression in human detrusor smooth muscle cells (SMCs).Human bladder SMCs were treated in vitro with TGF-beta1 and analyzed for changes in both proliferative and hypertrophic responses by cell number and volume measurements, as well as for alterations in extracellular matrix gene and protein expression by Northern blot and enzyme-linked immunosorbent assay.Proliferation of bladder SMCs was refractory to TGF-beta1, whereas the cells became hypertrophic upon TGF-beta1 treatment. The interstitial collagens, types I and III, were increased significantly in TGF-beta1-treated cultures in a dose-dependent manner. These increases were blocked in the presence of TGF-beta1 neutralizing antibody and also when cultures were treated with the protein synthesis inhibitor cycloheximide, indicating that new protein synthesis is necessary for upregulation of the interstitial collagens. Messenger ribonucleic acid transcripts for both the COL1A1 and COL3A1 genes were elevated at 4, 6, and 24 hours in TGF-beta1-treated cultures, preceding the expression of the collagenous protein, showing that TGF-beta1 effects on bladder smooth muscle occur, at least in part, at the transcriptional level.These results indicate that human bladder SMCs have the potential to mediate both a hypertrophic and fibrotic response upon TGF-beta1 stimulation.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [16] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| [17] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
| {{custom_ref.label}} |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
PDF(4624 KB)
/
| 〈 |
|
〉 |
