Macrophages, Myofibroblasts, and Extracellular Matrix Accumulation in Interstitial Fibrosis of Chronic Progressive Nephropathy in Aged Rats

1998 ◽  
Vol 35 (5) ◽  
pp. 352-360 ◽  
Author(s):  
S. Nakatsuji ◽  
J. Yamate ◽  
S. Sakuma
Keyword(s):  
Extracellular Matrix ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Basement Membranes ◽  
Collagen Type Iv ◽  
Renal Tubules ◽  
Renal Interstitial Fibrosis ◽  
Ecm Proteins ◽  
Grade 3

Progressive renal fibrosis is considered to be the final common pathway leading to chronic renal failure. Macrophages are thought to play a role in the induction of the myofibroblasts that produce extracellular matrix (ECM) proteins in renal interstitial fibrosis. We immunohistochemically investigated the relationship between infiltrating macrophages and myofibroblast development in chronic progressive nephropathy (CPN) in 24 month-old male F344 rats, and we also analyzed components of ECM proteins using immunofluorescence microscopy. According to histomorphologic criteria for severity, described elsewhere, rats with CPN were divided into grade 1 ( n = 20), grade 2 ( n = 34), grade 3 ( n = 10), and grade 4 ( n = 6). The ratio of fibrotic tissues per unit area, determined by morphometric analysis, was increased with advancing grade of nephropathy. The number of interstitial macrophages continued to be increased gradually, with a peak in grade 4. α-smooth muscle actin-positive myofibroblasts developed, surrounding the regenerating renal tubules in conjunction with the fibrotic areas. The number of the myofibroblasts was also increased, with a peak in grade 3, but in grade 4, it was slightly decreased. There was a significant relationship between the number of infiltrating macrophages and the degree of interstitial fibrosis ( r = 0.802; P < 0.05). These observations suggest that macrophages and myofibroblasts might be key cells in fibrogenesis in CPN. However, there was no significant correlation between the numbers of macrophages and myofibroblasts ( r = 0.198; P>0.05), although a significant relation between these cells has been reported in the early stages of experimental rat renal fibrosis. Immunostaining for collagen type IV demonstrated increased expression in thickened tubular basement membranes. Abnormal depositions of collagen types I and III, fibronectin, and tenascin were also observed in fibrotic areas adjacent to dilated or atrophic tubules with thickened basement membranes. These ECM proteins were increased in conjunction with the grade of nephropathy, suggesting that ECM accumulation might contribute to progression of renal interstitial fibrosis.

Delayed administration of hepatocyte growth factor reduces renal fibrosis in obstructive nephropathy

2003 ◽  
Vol 284 (2) ◽  
pp. F349-F357 ◽  
Author(s):  
Junwei Yang ◽  
Youhua Liu
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β1 ◽  
Muscle Actin ◽  
Renal Interstitial Fibrosis ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF) is a renotropic protein that elicits antifibrogenic activity by preventing the activation of matrix-producing myofibroblast cells in animal models of chronic renal diseases. However, whether a delayed administration of HGF can still attenuate renal fibrosis remains uncertain. In this study, we examined the therapeutic potential of exogenous HGF on an established renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Three days after UUO, the obstructed kidneys displayed interstitial fibrotic lesions with characteristic features of an established renal fibrosis, as manifested by myofibroblast activation, fibronectin overexpression, interstitial matrix deposition, and transforming growth factor-β1 upregulation. Beginning at this time point, administration of recombinant HGF into mice by intravenous injections for 11 days markedly suppressed the progression of renal interstitial fibrosis. HGF significantly suppressed renal α-smooth muscle actin expression, total kidney collagen contents, interstitial matrix components, such as fibronectin, and renal expression of transforming growth factor-β1 and its type I receptor. Compared with the starting point (3 days after UUO), HGF treatment largely blunted the progression of myofibroblast accumulation and collagen deposition but did not reverse it. Delayed administration of HGF also suppressed the myofibroblastic transdifferentiation from tubular epithelial cells in vitro, as demonstrated by a decline in α-smooth muscle actin and fibronectin expression. These results suggest that exogenous HGF exhibits potent therapeutic effects on retarding the progression of an established renal fibrosis.

LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

2021 ◽  
pp. 1-11
Author(s):  
Ting-Ting Liu ◽  
Ran Luo ◽  
Yi Yang ◽  
Yi-Chun Cheng ◽  
Dan Chang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Tube Formation ◽  
Renal Interstitial Fibrosis ◽  
Genetic Ablation ◽  
Capillary Rarefaction ◽  
Peritubular Capillaries ◽  
Renal Tubular

<b><i>Introduction:</i></b> Increasing evidence has demonstrated that loss of peritubular capillaries plays a critical role in renal interstitial fibrosis. Leucine-rich α2-glycoprotein-1 (LRG1) has been observed promoting angiogenesis in the ocular disease mouse model and myocardial infarction model. We aimed to explore the role of LRG1 in renal interstitial fibrosis. <b><i>Methods:</i></b> We analyzed the expression of LRG1 in the plasma and kidney of CKD patients by ELISA and immunohistochemistry. Relationships between the expression of LRG1 in plasma and kidney and renal fibrosis and inflammation were analyzed. Tube formation assay was used to detect the angiogenesis in the human umbilical vein endothelial cell lines (HUVECs). And real-time PCR was used to detect the mRNA expression of LRG1, inflammatory factors, renal tubular injury indicators, pro-fibrotic cytokines, and CD31. We examined the effects of genetic ablation of LRG1 on renal fibrosis induced by unilateral ureteral obstruction (UUO) mice model at day 7. <b><i>Results:</i></b> We demonstrated that the expression of LRG1 in renal tissues and plasma samples was upregulated in CKD patients. And the expression of LRG1 was elevated in human renal tubular epithelial cell line (HK-2) cells in response to the stimulation of TNF-α in vitro, and in kidney after UUO in vivo. The deficiency of the LRG1 gene aggravated renal fibrosis, inflammatory cells infiltration, and capillary rarefaction after UUO. In vitro, LRG1 promoted the tube formation of HUVEC cells. LRG1 inhibits fibronectin secretion induced by TGF-β1 in HK-2 and overexpression of LRG1 in HK-2 cells decreased fibronectin secretion. <b><i>Conclusion:</i></b> LRG1 may prevent renal fibrosis by inhibiting the secretion of inflammatory and pro-fibrotic cytokines and promoting angiogenesis.

scholarly journals Precision-Cut Kidney Slices as a Tool to Understand the Dynamics of Extracellular Matrix Remodeling in Renal Fibrosis

2016 ◽  
Vol 11 ◽  
pp. BMI.S38439 ◽  
Author(s):  
Federica Genovese ◽  
Zsolt S. Kàrpàti ◽  
Signe H. Nielsen ◽  
Morten A. Karsdal
Keyword(s):  
Extracellular Matrix ◽  
Collagen Type ◽  
Interstitial Fibrosis ◽  
Ex Vivo ◽  
Collagen Type I ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Renal Interstitial Fibrosis ◽  
Ex Vivo Model

The aim of this study was to set up an ex vivo model for renal interstitial fibrosis in order to investigate the extracellular matrix (ECM) turnover profile in the fibrotic kidney. We induced kidney fibrosis in fourteen 12-week-old male Sprague Dawley rats by unilateral ureteral obstruction (UUO) surgery of the right ureter. The left kidney (contralateral) was used as internal control. Six rats were sham operated and used as the control group. Rats were terminated two weeks after the surgery; the kidneys were excised and precision-cut kidney slices (PCKSs) were cultured for five days in serum-free medium. Markers of collagen type I formation (P1NP), collagen type I and III degradation (C1M and C3M), and α-smooth muscle actin (αSMA) were measured in the PCKS supernatants by enzyme-linked immunosorbent assay. P1NP, C1M, C3M, and α-SMA were increased up to 2- to 13-fold in supernatants of tissue slices from the UUO-ligated kidneys compared with the contralateral kidneys ( P < 0.001) and with the kidneys of sham-operated animals ( P < 0.0001). The markers could also reflect the level of fibrosis in different animals. The UUO PCKS ex vivo model provides a valuable translational tool for investigating the extracellular matrix remodeling associated with renal interstitial fibrosis.

scholarly journals Signaling Pathways Involved in Diabetic Renal Fibrosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuqing Zhang ◽  
De Jin ◽  
Xiaomin Kang ◽  
Rongrong Zhou ◽  
Yuting Sun ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Interstitial Fibrosis ◽  
New Drugs ◽  
Therapeutic Effects ◽  
Renal Interstitial Fibrosis ◽  
Notch Pathways ◽  
Stage Renal Disease ◽  
End Stage

Diabetic kidney disease (DKD), as the most common complication of diabetes mellitus (DM), is the major cause of end-stage renal disease (ESRD). Renal interstitial fibrosis is a crucial metabolic change in the late stage of DKD, which is always considered to be complex and irreversible. In this review, we discuss the pathological mechanisms of diabetic renal fibrosis and discussed some signaling pathways that are closely related to it, such as the TGF-β, MAPK, Wnt/β-catenin, PI3K/Akt, JAK/STAT, and Notch pathways. The cross-talks among these pathways were then discussed to elucidate the complicated cascade behind the tubulointerstitial fibrosis. Finally, we summarized the new drugs with potential therapeutic effects on renal fibrosis and listed related clinical trials. The purpose of this review is to elucidate the mechanisms and related pathways of renal fibrosis in DKD and to provide novel therapeutic intervention insights for clinical research to delay the progression of renal fibrosis.

scholarly journals Differential expression of parietal epithelial cell and podocyte extracellular matrix proteins in focal segmental glomerulosclerosis and diabetic nephropathy

2019 ◽  
Vol 317 (6) ◽  
pp. F1680-F1694 ◽  
Author(s):  
Gek Cher Chan ◽  
Diana G. Eng ◽  
Jeffrey H. Miner ◽  
Charles E. Alpers ◽  
Kelly Hudkins ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Diabetic Nephropathy ◽  
Epithelial Cell ◽  
Focal Segmental Glomerulosclerosis ◽  
Collagen Type ◽  
Collagen Type Iv ◽  
Type Iv ◽  
Ecm Proteins ◽  
Segmental Glomerulosclerosis ◽  
Parietal Epithelial Cell

In healthy glomeruli, parietal epithelial cell (PEC)-derived extracellular matrix (ECM) proteins include laminin-β1, perlecan, and collagen type IV-α2 and podocyte-specific ECM proteins include laminin-β2, agrin, and collagen type IV-α4. This study aimed to define individual ECM protein isoform expression by PECs in both experimental and human focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN) and to determine if changes were CD44 dependent. In experimental FSGS induced with a cytotoxic podocyte antibody and in the BTBR ob/ob mouse model of DN, PEC-derived protein staining was significantly increased in PECs. Dual staining also showed de novo expression of the podocyte-specific ECM proteins laminin-β2 and agrin in PECs. Similar findings were observed in biopsies from patients with FSGS and DN. Increases in individual ECM proteins colocalized with CD44 in PECs in disease. To determine the role of CD44, FSGS was induced in CD44−/− and CD44+/+ mice. PEC staining for perlecan, collagen type IV-α2, laminin-β2, and agrin were significantly lower in diseased CD44−/− mice compared with diseased CD44+/+ mice. These results show that in experimental and human FSGS and DN, PECs typically in an activated state, produce both PEC-derived and podocyte-specific ECM protein isoforms, and that the majority of these changes were dependent on CD44.

scholarly journals Collagen content and extracellular matrix cause cytoskeletal remodelling in pancreatic fibroblasts

2019 ◽  
Vol 16 (154) ◽  
pp. 20190226 ◽  
Author(s):  
Andreas Stylianou ◽  
Vasiliki Gkretsi ◽  
Maria Louca ◽  
Lefteris C. Zacharia ◽  
Triantafyllos Stylianopoulos
Keyword(s):  
Extracellular Matrix ◽  
Stromal Cells ◽  
Smooth Muscle Actin ◽  
Coiled Coil ◽  
Substrate Stiffness ◽  
Tumour Invasion ◽  
Alpha Smooth Muscle Actin ◽  
Desmoplastic Reaction ◽  
Young’S Moduli ◽  
Ecm Proteins

In many solid tumours a desmoplastic reaction takes place, which results in tumour tissue stiffening due to the extensive production of extracellular matrix (ECM) proteins, such as collagen, by stromal cells, mainly fibroblasts (FBs) and cancer-associated fibroblasts (CAFs). In this study, we investigated the effect of collagen stiffness on pancreatic FBs and CAFs, particularly on specific cytoskeleton properties and gene expression involved in tumour invasion. We found that cells become stiffer when they are cultured on stiff substrates and express higher levels of alpha-smooth muscle actin (α-SMA). Also, it was confirmed that on stiff substrates, CAFs are softer than FBs, while on soft substrates they have comparable Young's moduli. Furthermore, the number of spread FBs and CAFs was higher in stiffer substrates, which was also confirmed by Ras-related C3 botulinum toxin substrate 1 ( RAC1 ) mRNA expression, which mediates cell spreading. Although stress fibres in FBs become more oriented on stiff substrates, CAFs have oriented stress fibres regardless of substrate stiffness. Subsequently, we demonstrated that cells' invasion has a differential response to stiffness, which was associated with regulation of Ras homologue family member ( RhoA ) and Rho-associated, coiled-coil containing protein kinase 1 ( ROCK-1 ) mRNA expression. Overall, our results demonstrate that collagen stiffness modulates FBs and CAFs cytoskeleton remodelling and alters their invasion properties.

Pterostilbene, a Bioactive Component of Blueberries, Alleviates Renal Interstitial Fibrosis by Inhibiting Macrophage-Myofibroblast Transition

2020 ◽  
Vol 48 (07) ◽  
pp. 1715-1729
Author(s):  
Yanhuan Feng ◽  
Fan Guo ◽  
Hongxia Mai ◽  
Jing Liu ◽  
Zijing Xia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Renal Fibrosis ◽  
Transcriptional Activity ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Rna Seq ◽  
Renal Interstitial Fibrosis ◽  
Bioactive Component

Pterostilbene (PTB) is a derivative of resveratrol present in grapes and blueberries. PTB is structurally similar to resveratrol, possessing properties such as being analgesic, anti-aging, antidiabetic, anti-inflammatory, anti-obesity, anti-oxidation, cholesterol-reductive, and neuroprotective. However, there have not been reports on the effect of PTB on macrophage-myofibroblast transition (MMT) induced fibrosis in kidney. In this study, we investigated the antifibrotic effects of PTB on the in vivo mouse unilateral ureteral obstruction (UUO) model and in vitro MMT cells. Kidneys subjected to UUO with PTB treatment were collected for the investigation of PTB mediating MMT derived renal interstitial fibrosis. We conducted kidney RNA-seq transcriptomes and TGF-[Formula: see text]1-induced bone marrow-derived macrophages assays to determine the mechanisms of PTB. We found that PTB treatment suppressed the interstitial fibrosis in UUO mice. PTB also attenuated the number of MMT cells in vivo and in vitro. The transcriptomic analysis showed that CXCL10 may play a central role in the process of PTB-treated renal fibrosis. The siRNA-mediated CXCL10 knockdown decreased the number of MMT cells in TGF-[Formula: see text]1-induced bone marrow-derived macrophages. Our results suggested that PTB attenuated renal interstitial fibrosis by mediating MMT by regulating transcriptional activity of CXCL10.

Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice

2016 ◽  
Vol 130 (19) ◽  
pp. 1727-1739 ◽  
Author(s):  
Akiko Tanino ◽  
Takafumi Okura ◽  
Tomoaki Nagao ◽  
Masayoshi Kukida ◽  
Zuowei Pei ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Rat Kidney ◽  
In Vitro Study ◽  
Dependent Manner ◽  
Renal Interstitial Fibrosis

Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon γ-inducing factor. Aldosterone plays a central role in the regulation of sodium and potassium homoeostasis by binding to the mineralocorticoid receptor and contributes to kidney and cardiovascular damage. Aldosterone has been reported to induce IL-18, resulting in cardiac fibrosis with induced IL-18-mediated osteopontin (OPN). We therefore hypothesized that aldosterone-induced renal fibrosis via OPN may be mediated by IL-18. To verify this hypothesis, we compared mice deficient in IL-18 and wild-type (WT) mice in a model of aldosterone/salt-induced hypertension. IL-18−/− and C57BL/6 WT mice were used for the uninephrectomized aldosterone/salt hypertensive model, whereas NRK-52E cells (rat kidney epithelial cells) were used in an in vitro model. In the present in vivo study, IL-18 protein expression was localized in medullary tubules in the WT mice, whereas in aldosterone-infused WT mice this expression was up-regulated markedly in the proximal tubules, especially in injured and dilated tubules. This renal damage caused by aldosterone was attenuated significantly by IL-18 knockout with down-regulation of OPN expression. In the present in vitro study, aldosterone directly induced IL-18 gene expression in renal tubular epithelial cells in a concentration- and time-dependent manner. These effects were inhibited completely by spironolactone. IL-18 may be a key mediator of aldosterone-induced renal fibrosis by inducing OPN, thereby exacerbating renal interstitial fibrosis. Inhibition of IL-18 may therefore provide a potential target for therapeutic intervention aimed at preventing the progression of renal injury.

scholarly journals Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis

Gut ◽  
1999 ◽  
Vol 44 (4) ◽  
pp. 534-541 ◽  
Author(s):  
M V Apte ◽  
P S Haber ◽  
S J Darby ◽  
S C Rodgers ◽  
G W McCaughan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Collagen Synthesis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Oxidant Stress ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Cell Counts ◽  
Ecm Proteins

BACKGROUNDThe pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells play a major role in fibrogenesis by synthesising increased amounts of collagen and other extracellular matrix (ECM) proteins when activated by profibrogenic mediators such as cytokines and oxidant stress.AIMSTo determine whether cultured rat pancreatic stellate cells produce collagen and other ECM proteins, and exhibit signs of activation when exposed to the cytokines platelet derived growth factor (PDGF) or transforming growth factor β (TGF-β).METHODSCultured pancreatic stellate cells were immunostained for the ECM proteins procollagen III, collagen I, laminin, and fibronectin using specific polyclonal antibodies. For cytokine studies, triplicate wells of cells were incubated with increasing concentrations of PDGF or TGF-β.RESULTSCultured pancreatic stellate cells stained strongly positive for all ECM proteins tested. Incubation of cells with 1, 5, and 10 ng/ml PDGF led to a significant dose related increase in cell counts as well as in the incorporation of3H-thymidine into DNA. Stellate cells exposed to 0.25, 0.5, and 1 ng/ml TGF-β showed a dose dependent increase in α smooth muscle actin expression and increased collagen synthesis. In addition, TGF-β increased the expression of PDGF receptors on stellate cells.CONCLUSIONSPancreatic stellate cells produce collagen and other extracellular matrix proteins, and respond to the cytokines PDGF and TGF-β by increased proliferation and increased collagen synthesis. These results suggest an important role for stellate cells in pancreatic fibrogenesis.

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