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1.
A major feature of the injury sustained by the kidney during obstructive nephropathy is a profound induction of apoptosis in the tubular epithelium. In this study, we explored the central roles of mitochondria and the mechanism of the protective effect of the mitochondrial targeted peptides in tubular cell apoptosis and interstitial fibrosis during obstructive nephropathy. Unilateral ureter obstruction (UUO) was performed on rats, and the animals were randomly assigned to intravenous treatment with normal saline, rat serum albumin (RSA), or HOCl-rat serum albumin (HOCl-RSA) in the presence or absence of SS-31. A sham-operation control group was set up by left ureteral dissociation but not ligation. Compared with the control group, UUO animals displayed fibrotic abnormalities, accompanied by increased expression of collagen-I, fibronectin, α-SMA protein and mRNA in the renal interstitium. They also displayed oxidative stress, as evidenced by increased levels of HOCl-alb, TBARS, and mitochondrial reactive oxygen species (ROS) and a decrease in MnSOD activity in the renal homogenate. Damage to mitochondrial structure and functions was observed, as evidenced by a decrease in the mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and release of cytochrome C (cyto C) from the mitochondria to the cytoplasm. These changes were accompanied by activation of caspase-3, caspase-7, caspase-9, and PARP-1 and increased apoptotic cells in the proximal tubules. HOCl-RSA challenge further exacerbated the above biological effects in UUO animals, but these effects were prevented by administration of SS-31. These data suggested that accumulation of HOCl-alb may promote tubular cell apoptosis and interstitial fibrosis, probably related to mitochondrial oxidative stress and damage, and that SS-31 might contribute to apoptotic pathway suppression via scavenging of ROS in the mitochondria.  相似文献   

2.
Unilateral ureteral obstruction (UUO) is the most widely used animal model of progressive renal disease. Although renal interstitial fibrosis is commonly used as an end point, recent studies reveal that obstructive injury to the glomerulotubular junction leads to the formation of atubular glomeruli. To quantitate the effects of UUO on the remainder of the nephron, renal tubular and interstitial responses were characterized in mice 7 and 14 days after UUO or sham operation under anesthesia. Fractional proximal tubular mass, cell proliferation, and cell death were measured by morphometry. Superoxide formation was identified by nitro blue tetrazolium, and oxidant injury was localized by 4-hydroxynonenol and 8-hydroxydeoxyguanosine. Fractional areas of renal vasculature, interstitial collagen, α-smooth muscle actin, and fibronectin were also measured. After 14 days of UUO, the obstructed kidney loses 19% of parenchymal mass, with a 65% reduction in proximal tubular mass. Superoxide formation is localized to proximal tubules, which undergo oxidant injury, apoptosis, necrosis, and autophagy, with widespread mitochondrial loss, resulting in tubular collapse. In contrast, mitosis and apoptosis increase in dilated collecting ducts, which remain patent through epithelial cell remodeling. Relative vascular volume fraction does not change, and interstitial matrix components do not exceed 15% of total volume fraction of the obstructed kidney. These unique proximal and distal nephron cellular responses reflect differential "fight-or-flight" responses to obstructive injury and provide earlier indexes of renal injury than do interstitial compartment responses. Therapies to prevent or retard progression of renal disease should include targeting proximal tubule injury as well as interstitial fibrosis.  相似文献   

3.
The temporal relationship between changes in cytosolic free calcium and proximal tubular function was examined in rats following 24 h of unilateral and bilateral ureteral obstruction. Immediately after release of unilateral ureteral obstruction, proximal tubular functions were found to be normal. Cytosolic free calcium in isolated proximal tubules of the ureteral obstructed and contralateral kidneys were 160 +/- 8 and 172 +/- 15 nM, respectively. On the 7th day after release, cytosolic free calcium was not different from the sham control value (135 +/- 6 vs. 149 +/- 7 nM). In contrast, immediately after release of bilateral ureteral obstruction, cytosolic free calcium was increased significantly to 219 +/- 6 from 139 +/- 9 nM in sham-operated controls. Subsequent declines in cytosolic free calcium to 196 +/- 15 and 148 +/- 7 nM were observed at 3 and 7 days after release of bilateral ureteral obstruction, respectively. Over this period, renal tubular functions gradually returned to normal. Changes in cytosolic free calcium correlate well with the reported improvement in renal tubular function after release of bilateral ureteral obstruction. Therefore, one possible mechanism for the impairment of tubular function observed in bilateral ureteral obstruction may be an increase in cytosolic free calcium.  相似文献   

4.
Acute pyelonephritis was induced in rats by temporary unilateral ureteric obstruction and the intravenous injection of Escherichia coli. Animals were sacrificed 48 h after infection and changes in renal cortical tubules due to the presence of bacteria were studied. Bacteria appeared and multiplied in the tubular lumina and proximal tubular epithelial cells endocytosed the microorganisms in large numbers. Coalescence of phagosomes with lysosomes resulted in the surrounding of engulfed bacteria with acid phosphatase. However, the lysosomal apparatus of the cells did not eliminate Escherichia coli since the bacteria multiplied within phagosomes and destroyed the normal cell architecture. The peritubular interstitial inflammatory infiltrate caused ischemia of tubules, enhancing bacterial damage to the proximal tubules. The cytoplasm of the injured tubular cells was sometimes detached from the basement membrane. Cells of the distal tubules and collecting ducts did not show significant endocytosis or bacterial tubular damage.  相似文献   

5.
小熊猫肾脏和输尿管的组织学研究   总被引:2,自引:0,他引:2  
米志平  杨智  李平 《四川动物》2003,22(4):241-243
小熊猫的肾脏呈蚕豆形,表面光滑不分叶,只有1个肾锥体和1个肾盏,无肾盂。肾脏皮质内可见皮质迷路和髓放线。皮质迷路内有近曲小管、远曲小管和肾小体等结构。髓放线内有近端小管直部和远端小管直部。髓质可分为外髓和内髓两个区域。外髓有较多的集合管断面,少量的远端小管直部和细段,较多的直小血管束。内髓部位有大量的细段和乳头管。各种泌尿小管之间有少量的疏松结缔组织构成的间质,间质内有丰富的毛细血管。输尿管横切面呈圆形或卵圆形,管腔呈不规则的裂隙状。管壁由粘膜、肌肉层和外膜组成。并与大熊猫肾脏和输尿管的组织结构作了比较研究。  相似文献   

6.
Glomerular filtration rates in whole kidney and in outer, middle and inner cortical zones have previously been estimated by measuring the amount of iodinated Aprotinin, filtered and taken up in the first two thirds of the proximal convoluted tubules, in part positioned more superficial than the parent glomerulus. Thus, an appreciable amount of the absorbed Aprotinin may be located superficial to its filtration site and lead to an underestimate of glomerular filtration in deep cortical layers. Therefore, in this study we have measured the distance from the glomerulus to the center of proximal convoluted tubular ball and the site of Aprotinin uptake. Measurements were made on photos of Microfil-injected tubules and on camera lucida drawings of tubular transections from autoradiographs of nephrons containing both Microfil and iodinated Aprotinin. Both techniques showed that the center of the tubular ball was localized more superficial in all cortical layers. The average distance, in percent of cortical thickness, from all proximal convoluted tubular transections to the parent glomerulus was 9% in deep and 13% in middle and superficial cortex. Corresponding distances for tubular transections containing Aprotinin were 7 and 12%. Grain density in five reconstructed proximal convoluted tubules showed a continuous and exponential fall of Aprotinin along the uptake segment. The results may be used to estimate single nephron filtration rate from Aprotinin uptake and glomerular density in outer, middle, and inner cortex.  相似文献   

7.
Renal fibrosis is the final, common pathway of end-stage renal disease. Whether and how autophagy contributes to renal fibrosis remains unclear. Here we first detected persistent autophagy in kidney proximal tubules in the renal fibrosis model of unilateral ureteral obstruction (UUO) in mice. UUO-associated fibrosis was suppressed by pharmacological inhibitors of autophagy and also by kidney proximal tubule-specific knockout of autophagy-related 7 (PT-Atg7 KO). Consistently, proliferation and activation of fibroblasts, as indicated by the expression of ACTA2/α-smooth muscle actin and VIM (vimentin), was inhibited in PT-Atg7 KO mice, so was the accumulation of extracellular matrix components including FN1 (fibronectin 1) and collagen fibrils. Tubular atrophy, apoptosis, nephron loss, and interstitial macrophage infiltration were all inhibited in these mice. Moreover, these mice showed a specific suppression of the expression of a profibrotic factor FGF2 (fibroblast growth factor 2). In vitro, TGFB1 (transforming growth factor β 1) induced autophagy, apoptosis, and FN1 accumulation in primary proximal tubular cells. Inhibition of autophagy suppressed FN1 accumulation and apoptosis, while enhancement of autophagy increased TGFB1-induced-cell death. These results suggest that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO. The profibrotic function of autophagy is related to the regulation on tubular cell death, interstitial inflammation, and the production of profibrotic factors.  相似文献   

8.
AimsThe present study investigated whether transplantation of bone marrow-derived endothelial progenitor cells (BM-EPCs) in renal capillary network improves renal interstitial fibrosis in unilateral ureteral obstruction (UUO) model in mice.Main methodsEx vivo generated, characterized, and cultivated mice BM-EPCs were identified by their vasculogenic properties in vitro. BM-EPCs were labelled with carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) before transplantation. The animal models of UUO were used. Histological changes in renal tubular interstitium were observed with HE and Masson staining. The protein levels of vascular endothelial growth factor(VEGF), hypoxia inducible factor-1α (HIF-1α) and connective tissue growth factor (CTGF) were analyzed by western blotting and immunohistochemistry. Transforming growth factor-β1 (TGF-β1) was detected by immunohistochemistry. Peritubular capillary (PTC) density was determined by CD31 immunostaining.Key findingsTransplanted BM-EPCs were successfully incorporated into the capillary network in the obstructed kidney in vivo. UUO induced a significant decrease in VEGF levels and PTC density in the kidney tissue, which was accompanied by a significant increase in HIF-1α, CTGF and TGF-β1. Transplantation of BM-EPCs increased PTC density, VEGF expression and alleviated the development of renal interstitial fibrosis in UUO mice. No significant pathological changes were found in control mice.SignificanceThe reduction of PTC density and up-regulation of HIF-1α are the important mechanisms of interstitial fibrosis in UUO mice. BM-EPCs transplantation may increase the number of capillary density and alleviate the development of renal fibrosis in obstructive nephropathy in mice.  相似文献   

9.
In a light and electron microscopic study of the rat's kidney after obstruction of the renal vein or after subtotal nephrectomy the tubular basement membrane changes occurring during the ensuing atrophy of the tubules have been examined. Characteristically, they consist of diffuse widening, focal thickening with vesicular and granular inclusions, circumscribed dissolution, or reduplication of this structure. These observations have led to the conclusion that the tubular basement membrane is formed by both interstitial and tubular cells, although the interstitial cells contribute the greater share to its formation, maintenance and renewal. The thickening of the basement membrane taking place in tubular atrophy must, however, be attributed entirely to the interstitial cells.  相似文献   

10.
Experimental acute pyelonephritis was produced in rats by a combination of intravenous administration of Escherichia coli, strain IMRU-54, and temporary unilateral mechanical ureteral obstruction. Structural alterations of the renal medulla were studied by light and electron microscopy. Major cellular alterations occurred in the vasa recta. Tubular and interstitial cells demonstrated minimal alterations after the brief period of acute inflammation. Polymorphonuclear leukocytes within tubular lumina contained structures resembling E. coli in nonprotoplasts-like form. Numerous protoplast-like organisms, to the exclusion of any other structural forms, were detected within the interstitium of the inner medulla. Nonprotoplast-like structures resembling E. coli were rarely observed in interstitium of the inner medulla. Following relief of ureteral obstruction, clearance of acute inflammation was rapid. In conclusion, hemoatogenous acute pyelonephritis induced by E. coli, IMRU-54, is able to inflict cytological and ultrastructural damage to structural elements of the inner and outer medulla of rats. Vasa recta incurred prominent alterations in endothelia and basement membranes, whereas tubular epithelia and interstitial cells had relatively good structural preservation. The data suggest that intravenously administered E. coli is capable to revert to a protoplast-like structure in the inner medulla.  相似文献   

11.
Summary To identify the renal cortical tubular segments involved in tubulo-interstitial disease in formalin-fixed, paraffin-embedded percutaneous kidney biopsies, we developed multiple immunolabeling protocols using segment-specific tubular markers. The present study of biopsies from patients with minimal change or thin basement membrane nephropathy provides a baseline for interpretation of histopathology. Proximal tubules were stained either by the PAS reaction or by the biotinylated Phaseolus vulgaris erythroagglutinin (PHA-E)-streptavidin-gold-silver system (brush borders black). The anti-Tamm-Horsfall (THP) antibody-immunoperoxidase (aminoethylcarbazole, AEC-IPO), and anti-epidermal cytokeratins (ECK) antibodies-immunoalkaline-Fast Blue BB methods marked the distal straight tubules and the cortical collecting system red-brown and blue, respectively. When these immunolabelings were combined, the coapplication of AEC-PO-labeled peanut agglutinin (PNA) or anti-epithelial membrane antigen antibody-AEC-IPO technique (both are markers for distal nephron) visualized the apical membranes of distal convoluted tubules. In the protocol PHA-E + PNA + THP + ECK, the tubular basement membranes were outlined by the anti-laminin antibody-AEC-IPO staining, carried out simultaneously. The protocol PNA + THP + ECK + PAS was found to be a quite appropriate multiple immunolabeling method for the tubules, and is recommended for use as a tool in the study of tubulo-interstitial diseases.Abbreviations PAS periodic acid-Schiff reaction - PHAE Phaseolus vulgaris erythroagglutinin - PNA Peanut agglutinin - EMA epithelial membrane antigen - THP Tamm-Horsfall glycoprotein - ECK epidermal cytokeratins - PO peroxidase - Biot-PHA-E biotinylated PHA-E - APAAP complexes of alkaline phosphatase and mouse monoclonal anti-alkaline phosphatase - SWARI swine anti-rabbit immunoglobulins - FCS fetal calf serum - TBS Tris-buffered saline - AEC aminoethylcarbazole - DAB diaminobenzidine - FBBB Fast Blue BB - IA immunoalkaline - GL glomerulus - PT proximal tubule - DST distal straight tubule - DCT distal convoluted tubule - CCS cortical collecting system - CT connecting tubule - CD collecting duct  相似文献   

12.
Ochratoxin A (OTA) is a nephrotoxic and cancerogenic mycotoxin. There is epidemiological evidence that OTA exposition leads to cortical interstitial nephropathies in humans. However, virtually no data are available investigating the effect of OTA on renal cortical cells with respect to induction of nephropathy. Thus, we investigated whether OTA is able to induce changes of cellular properties potentially leading to interstitial nephropathy, using proximal tubular cell lines (OK, NRK-52E). OTA decreased cell number and cell protein time and dose dependently. Accordingly we investigated the effect of 100 nM or 1000 nM OTA. The decline of cell number after OTA exposure is due to necrosis and apoptosis, as measured by LDH release or DNA ladder formation and caspase-3 activation, respectively. OTA incubation of proximal tubular cells also resulted in a loss of epithelial tightness as determined by diffusion of FITC labeled inulin. Inflammation, fibrosis and epithelial-to-mesenchymal transition are described in chronic interstitial renal disease. Therefore, we also investigated the effect of OTA on NFkappaB activity, collagen secretion and generation of alpha smooth muscle actin. OTA alone was sufficient to induce the latter parameters in proximal tubular cells. Finally, OTA is a nephrotoxcic substance and elevated activity of mitogen activated protein kinases (MAPK) is described in nephropathies. As we investigated the effect of OTA on activity of ERK, JNK and p38 by ELISA, we found that OTA activates the MAPK measured dose dependently. In summary, OTA induced phenomena typical for chronic interstitial nephropathy, like loss of cells and epithelial tightness, necrosis and apoptosis as well as markers of inflammation, fibrosis and epithelial-to-mesenchymal transition in proximal tubular cells. Thus, we could show for the first time that OTA is able to induce key parameters of nephropathy in proximal tubular cells in culture. Moreover OTA interacts with MAPK and thus may exert its specific toxic actions.  相似文献   

13.
The main focus of the present investigation is to examine obstructed kidneys due to unilateral ureteral obstruction (UUO) model in adult mice using segment-specific tubular marker and to confirm the detailed morphological evaluation of UUO that is a typical model for the tubulointerstitial fibrosis which is an endpoint outcome of chronic renal diseases. Adult mice were subjected to UUO, and kidneys were harvested 1, 3, 7 days after surgical operation. Expansion of interstitial space both in the cortex and the medulla was confirmed 3 days after UUO by HE- and azan-staining. Interstitial fibrosis developed especially around dilated tubules. Immunohistochemistry for segment-specific antibodies revealed that the proximal tubules and the descending limb of Henle's loop did not dilate until 7 days after UUO, whereas initial dilation of the ascending limb of Henle's loop appeared to occur one day after surgery. The segment from the distal tubules to the collecting ducts began dilating one day after surgery and afterward significantly dilated. The downstream segment of nephron was involved in dilating earlier than the upstream of nephron in obstructed kidney examined in the present study. Moreover, the tubules accompanying apoptosis of tubular epithelia significantly dilated compared with those without apoptotic tubular epithelia. From the above-mentioned findings, we conclude that tubular dilatation of distal segment (from the ascending limb of Henle's loop to the collecting ducts) of nephron develops tubular epithelial apoptosis caused by accumulated urine, which would link to tubular disappearance and its replacement with fibrous tissue in UUO kidney of adult mice.  相似文献   

14.
Albumin has been identified in preparations of renal distal tubules and collecting ducts by mass spectrometry. This study aimed to establish whether albumin was a contaminant in those studies or actually present in the tubular cells, and if so, identify the albumin containing cells and commence exploration of the origin of the intracellular albumin. In addition to the expected proximal tubular albumin immunoreactivity, albumin was localized to mouse renal type-A intercalated cells and cells in the interstitium by three anti-albumin antibodies. Albumin did not colocalize with markers for early endosomes (EEA1), late endosomes/lysosomes (cathepsin D) or recycling endosomes (Rab11). Immuno-gold electron microscopy confirmed the presence of albumin-containing large spherical membrane associated bodies in the basal parts of intercalated cells. Message for albumin was detected in mouse renal cortex as well as in a wide variety of other tissues by RT-PCR, but was absent from isolated connecting tubules and cortical collecting ducts. Wild type I MDCK cells showed robust uptake of fluorescein-albumin from the basolateral side but not from the apical side when grown on permeable support. Only a subset of cells with low peanut agglutinin binding took up albumin. Albumin-aldosterone conjugates were also internalized from the basolateral side by MDCK cells. Aldosterone administration for 24 and 48 hours decreased albumin abundance in connecting tubules and cortical collecting ducts from mouse kidneys. We suggest that albumin is produced within the renal interstitium and taken up from the basolateral side by type-A intercalated cells by clathrin and dynamin independent pathways and speculate that the protein might act as a carrier of less water-soluble substances across the renal interstitium from the capillaries to the tubular cells.  相似文献   

15.
A renal tubular lesion was induced in male rats by giving them a culture homogenate or culture filtrate of Penicillium verrucosum var. cyclopium by gastric gavage for 20 days. The fungus was obtained from stored maize in an area of endemic nephropathy in Bulgaria. Changes in the proximal convoluted tubules were studied by light and electron microscopy. The lesion was confined to the pars recta in the outer stripe of the outer zone of the medulla. It consisted of degeneration and necrosis of epithelial cells, prominent karyomegaly, arrested mitotic divisions and production of binucleate and tetranucleate tubular cells. Two patterns of degeneration occurred with comparable frequency: a vesicular form with pyknotic nucleus and electron lucent degeneration. Nuclei of the epithelial cells in affected tubules contained segregated nucleoli. The necrotic cells were replaced by actively regenerating cells derived from adjacent viable epithelium. The similarity between the tubular lesions induced in rats and the changes found in patients with Balkan endemic nephropathy is discussed.  相似文献   

16.
Previous studies reported that RAGE participated in the process of kidney fibrosis, but the function and regulation pathway of RAGE in proximal tubular cells in this process remains unclear. Here, we found that expression of RAGE was increased by TGF-β1 treatment and unilateral ureteral obstruction (UUO). Knock down of RAGE ameliorated renal fibrosis by TGF-β1 treatment, the expression of vimentin, Collagen I&III, and fibronectin are decreased. Mechanistically, RAGE mediated TGF-β1-induced phosphorylation of Stat3 and directly upregulated the Atg7 to increase the level of autophagy, and ultimately resulting in renal fibrosis. Furthermore, PT-RAGE-KO mice reduced kidney fibrosis in UUO model via inhibiting Stat3/Atg7 axis by knocking down RAGE. Furthermore, the above findings were confirmed in kidney of patients with obstructive nephropathy. Collectively, RAGE in proximal tubular cells promotes the autophagy to increase renal fibrosis via upregulation of Stat3/Atg7 axis.Subject terms: Autophagy, Urogenital diseases  相似文献   

17.
Proximal convoluted, proximal straight, and cortical collecting tubular segments isolated from rabbit kidney were perfused with I 125-labeled rabbit serum albumin (RSA-I 125) in ultrafiltrate of serum for up to 3 hr After perfusion, the segments were fixed with glutaraldehyde, embedded in Epon, and either counted with a gamma spectrometer to quantitate protein accumulation or analyzed by electron microscope radioautography to sequentially localize radioactivity Proximal convoluted and proximal straight segments accumulate RSA-I 125 nearly linearly as a function of time whereas cortical collecting segments do not accumulate measurable amounts of protein. The rate of accumulation of RSA-I 125 in the proximal convoluted tubule is 2 6 times as great as that in the proximal straight tubule. Electron microscope radioautography of the isolated proximal tubule demonstrated that RSA-I 125 is taken up via small apical vesicles and tubular invaginations, released into large cytoplasmic vacuoles, and finally concentrated in membrane-bounded structures, some of which are acid phosphatase positive These results show that albumin is absorbed by proximal tubules and may be degraded intracellularly within lysosomes. In addition, less radioactivity was located at all times over the lateral intercellular and basilar labyrinthine spaces, suggesting that labeled albumin and/or its breakdown products may be transported across the peritubular cell membrane.  相似文献   

18.
为观察化瘀解毒中药对梗阻性肾病巨噬细胞浸润的影响及作用机制。将48只健康雄性Wistar大鼠随机分为假手术组、模型组、依普利酮组、中药组,每组12只。除假手术组外,其余大鼠结扎单侧输尿管(UUO)复制肾间质纤维化动物模型。治疗组分别给以依普利酮(100 mg/kg/d加入饲料喂养)和化瘀解毒中药煎剂(14 g/kg/d灌胃)。10 d后摘取肾脏,观察大鼠肾脏组织病理改变。免疫组化法标记巨噬细胞浸润,免疫组化、Western Blot方法检测血清和糖皮质激素诱导蛋白激酶1(SGK-1)、单核细胞趋化蛋白-1(MCP-1)、白细胞介素-1(IL-1)、肿瘤坏死因子-α(TNF-α)的表达。肾脏病理显示,UUO组大鼠肾脏有明显的肾小管扩张及上皮细胞脱落,间质巨噬细胞浸润增多和细胞外基质(ECM)大量积聚,SGK-1、MCP-1、IL-1、TNF-α表达明显增强。化瘀解毒中药可明显减轻UUO大鼠肾脏巨噬细胞等炎性细胞浸润和ECM沉积,下调SGK-1、MCP-1、IL-1、TNF-α表达。以上结果说明化瘀解毒中药可抑制梗阻性肾病诱导的巨噬细胞浸润,减轻肾脏炎性损伤。  相似文献   

19.
Fluorofenidone (FD) is a novel pyridone agent with significant antifibrotic effects in vitro. The purpose of this study is to investigate the effects of FD on renal interstitial fibrosis in rats with obstructive nephropathy caused by unilateral ureteral obstruction (UUO). With pirfenidone (PD, 500 mg/kg/day) and enalapril (10 mg/kg/day) as the positive treatment controls, the rats in different experimental groups were administered with FD (500 mg/kg/day) from day 4 to day 14 after UUO. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and type III collagen, transforming growth factor-β(1) (TGF-β(1)), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), α-smooth muscle actin (α-SMA), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed. FD treatment significantly attenuated the prominently increased scores of tubulointerstitial injury, interstitial collagen deposition, and protein expression of type I and type III collagen in ureter-obstructed kidneys, respectively. As compared with untreated rats, FD also significantly reduced the expression of α-SMA, TGF-β(1), CTGF, PDGF, and inhibitor of TIMP-1 in the obstructed kidneys. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy through its regulation on fibrogenic growth factors, tubular cell transdifferentiation, and extracellular matrix.  相似文献   

20.
Renal interstitial fibrosis is a common renal injury resulted from a variety of chronic kidney conditions and an array of factors. We report here that Notch3 is a potential contributor. In comparison to 6 healthy individuals, a robust elevation of Notch3 expression was observed in the renal tubular epithelial cells of 18 patients with obstructive nephropathy. In a rat unilateral ureteral obstruction (UUO) model which mimics the human disease, Notch3 upregulation closely followed the course of renal injury, renal fibrosis, TGFβ expression, and alpha-smooth muscle actin (α-SMA) expression, suggesting a role of Notch3 in promoting tubulointerstitial fibrosis. This possibility was supported by the observation that TGFβ, the major renal fibrogenic cytokine, stimulated Notch3 expression in human proximal tubule epithelial HK-2 cells. TGFβ enhanced the activation of ERK, p38, but not JNK MAP kinases in HK-2 cells. While inhibition of p38 activation using SB203580 did not affect TGFβ-induced Notch3 expression, inhibition of ERK activation with a MEK1 inhibitor PD98059 dramatically reduced the event. Furthermore, enforced ERK activation through overexpression of the constitutively active MEK1 mutant MEK1Q56P upregulated Notch3 expression in HK-2 cells, and PD98059 reduced ERK activation and Notch3 expression in HK-2 cells expressing MEK1Q56P. Collectively, we provide the first clinical evidence for Notch3 upregulation in patients with obstructive nephropathy; the upregulation is likely mediated through the TGFβ-ERK pathway. This study suggests that Notch3 upregulation contributes to renal injury caused by obstructive nephropathy, which could be prevented or delayed through ERK inhibition.  相似文献   

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