scholarly journals Renal growth responses to acute and chronic injury: routes to therapeutic intervention.

1992 ◽  
Vol 2 (10) ◽  
pp. S206
Author(s):  
L G Fine ◽  
J T Norman
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Interstitial Fibrosis ◽  
Renal Diseases ◽  
Growth Responses ◽  
Glomerular Injury ◽  
Tubular Atrophy ◽  
Matrix Deposition ◽  
Extracellular Matrix Deposition ◽  
Diseased Kidney

Knowledge of the control of cell growth and extracellular matrix deposition has assumed center stage in the understanding of how the diseased kidney responds to injury. After acute tubular injury, there may be reversible, partial depolarization of renal cells or cell necrosis. The latter requires a regenerative response, which could be under the control of growth factors such as epidermal growth factor (EGF). Up-regulation of EGF receptors on viable cells provides the cell with an enhanced growth response despite a reduction in EGF production by the kidney. Acute glomerular injury involves a highly complex network of cytokines and growth inhibitors, the most important of which appear to be platelet-derived growth factor as a mitogen and transforming growth factor beta as an activator of extracellular matrix deposition. The long-term growth responses of the kidney to injury, reflected by chronic renal diseases, include tubular hypertrophy in those nephrons which are less affected by the primary disease. Tubular cell enlargement appears to proceed along a pathway that is different from the growth in cell size which precedes cell division, at least as indicated by a fundamentally different pattern of early gene expression. This pattern is not suggestive of a classical growth factor-initiated process. Other chronic changes that seem to correlate well with the progression of human disease are tubular atrophy and interstitial fibrosis. Growth factors produced by tubular cells may cause proliferation and matrix deposition by adjacent interstitial fibroblasts. A scheme is proposed in which low-grade ischemic injury to tubular cells, secondary to microvascular injury, leads to tubular atrophy, the release of growth factors, interstitial fibrosis, and the obliteration of peritubular capillaries. This would aggravate primary glomerular injury by compromising the vascular outflow from the glomerulus and would account for the long-recognized association between tubulo-interstitial injury and the progression of a variety of renal diseases. The use of growth factors to stimulate specific growth responses, antibodies, or inhibitory molecules to inhibit scarring generated by cytokines and the potential for genetic manipulation of the kidney provide future avenues for manipulating the growth response of the diseased kidney.

Carvacrol Ameliorates Transforming Growth Factor-β1-Induced Extracellular Matrix Deposition and Reduces Epithelial-Mesenchymal Transition by Regulating The Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway In Hk-2 Cells

2021 ◽  
Vol 19 (4) ◽  
pp. 501-507
Author(s):  
Yunhe Gu ◽  
Peiyao Guo ◽  
Guangbiao Xu
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β1 ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Extracellular Matrix Deposition ◽  
Dose Dependent

Transforming growth factor-β1 promotes excessive extracellular matrix deposition and epithelial-mesenchymal transition of tubular epithelial cells, thus stimulating the progression of renal fibrosis. Carvacrol has been shown to alleviate cardiac and liver fibrosis and attenuate renal injury. However, the role of carvacrol on renal fibrosis has not been examined. First, measurements using Cell Counting Kit-8 showed that carvacrol reduced cell viability of tubular epithelial cell line HK-2 in a dose-dependent fashion. Second, transforming growth factor-β1 induced excessive extracellular matrix deposition in HK-2 cells with enhanced collagen I, collagen IV, and fibronectin expression. However, carvacrol decreased the expression of collagen I, collagen IV in a dose-dependent manner and fibronectin to attenuate the extracellular matrix deposition in HK-2. Third, carvacrol attenuated TGF-β1-induced decrease of E-cadherin and increase of snail, vimentin, and alpha-smooth muscle actin in HK-2 cells. Transforming growth factor-β1-induced increase in PI3K and AKT phosphorylation in HK-2 were also reversed by carvacrol. Collectively, carvacrol ameliorates renal fibrosis through inhibition of transforming growth factor-β1-induced extracellular matrix deposition and epithelial-mesenchymal transition of HK-2 cells, providing potential therapy for the treatment of renal fibrosis.

Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?

2002 ◽  
Vol 283 (1) ◽  
pp. L1-L11 ◽  
Author(s):  
Margaret K. Winkler ◽  
John L. Fowlkes
Keyword(s):  
Acute Lung Injury ◽  
Growth Factors ◽  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Inflammatory Cells ◽  
Transforming Growth Factor Β ◽  
Target Cells

Chronic lung disease due to interstitial fibrosis can be a consequence of acute lung injury and inflammation. The inflammatory response is mediated through the migration of inflammatory cells, actions of proinflammatory cytokines, and the secretion of matrix-degrading proteinases. After the initial inflammatory insult, successful healing of the lung may occur, or alternatively, dysregulated tissue repair can result in scarring and fibrosis. On the basis of recent insights into the mechanisms underlying acute lung injury and its long-term consequences, data suggest that proteinases, such as the matrix metalloproteinases (MMPs), may not only be involved in the breakdown and remodeling that occurs during the injury but may also cause the release of growth factors and cytokines known to influence growth and differentiation of target cells within the lung. Through the release of and activation of fibrosis-promoting cytokines and growth factors such as transforming growth factor-β1, tumor necrosis factor-α, and insulin-like growth factors by MMPs, we propose that these metalloproteinases may be integral to the initiation and progression of pulmonary fibrosis.

scholarly journals Urinary chemokine C-X-C motif ligand 16 and endostatin as predictors of tubulointerstitial fibrosis in patients with advanced diabetic kidney disease

2019 ◽  
Author(s):  
Yu Ho Lee ◽  
Ki Pyo Kim ◽  
Sun-Hwa Park ◽  
Dong-Jin Kim ◽  
Yang-Gyun Kim ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Interstitial Fibrosis ◽  
Renal Outcome ◽  
Enzyme Linked Immunosorbent Assay ◽  
Glomerular Injury ◽  
Tubular Atrophy ◽  
Diabetic Kidney ◽  
Cytokines And Chemokines ◽  
Pathologic Features

Abstract Background Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. Methods Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. Results Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P < 0.001) and poor renal outcome (P = 0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P = 0.001 and P < 0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P < 0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070–3.455, P = 0.029). Conclusions Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.

V. TGF-β signaling pathways

2000 ◽  
Vol 279 (5) ◽  
pp. G845-G850 ◽  
Author(s):  
Rebecca G. Wells
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Matrix Effects ◽  
Matrix Deposition ◽  
Peptide Growth Factor ◽  
Wide Range ◽  
The Matrix ◽  
Extracellular Matrix Deposition ◽  
Generating Matrix

Transforming growth factor (TGF)-β is a multifunctional peptide growth factor with a wide range of potential effects on growth, differentiation, extracellular matrix deposition, and the immune response. General TGF-β signaling pathways have been described in detail over the last several years, but factors that determine the nature of the TGF-β response are poorly understood. In particular, signaling pathways that specifically mediate the matrix effects of TGF-β have received little attention, although they will be important therapeutic targets in the treatment of pathological fibrosis. This themes article focuses on TGF-β signaling and highlights potential points for generating matrix-specific responses.

scholarly journals Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?

2016 ◽  
Vol 242 (4) ◽  
pp. 374-383 ◽  
Author(s):  
Renu Agarwal ◽  
Puneet Agarwal
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factors ◽  
Growth Factors ◽  
Molecular Targets ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Matrix Deposition ◽  
Mitogen Activated Protein ◽  
Extracellular Matrix Deposition

Disturbances of extracellular matrix homeostasis are associated with a number of pathological conditions. The ability of extracellular matrix to provide contextual information and hence control the individual or collective cellular behavior is increasingly being recognized. Hence, newer therapeutic approaches targeting extracellular matrix remodeling are widely investigated. We reviewed the current literature showing the effects of resveratrol on various aspects of extracellular matrix remodeling. This review presents a summary of the effects of resveratrol on extracellular matrix deposition and breakdown. Mechanisms of action of resveratrol in extracellular matrix deposition involving growth factors and their signaling pathways are discussed. Involvement of phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways and role of transcription factors and sirtuins on the effects of resveratrol on extracellular matrix homeostasis are summarized. It is evident from the literature presented in this review that resveratrol has significant effects on both the synthesis and breakdown of extracellular matrix. The major molecular targets of the action of resveratrol are growth factors and their signaling pathways, phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways, transcription factors, and SIRT-1. The effects of resveratrol on extracellular matrix and the molecular targets appear to be related to experimental models, experimental environment as well as the doses.

scholarly journals Preclinical Study of DNA-Recognized Peptide Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Progressive Renal Diseases in Common Marmoset

2019 ◽  
Author(s):  
Masari Otsuki ◽  
Noboru Fukuda ◽  
Takashi Inoue ◽  
Takayuki Mineshige ◽  
Tomoyasu Otsuki ◽  
...  
Keyword(s):  
Target Genes ◽  
Interstitial Fibrosis ◽  
Renal Medulla ◽  
Common Marmoset ◽  
Preclinical Study ◽  
Renal Diseases ◽  
Glomerular Injury ◽  
Tubulointerstitial Injury ◽  
Injury Score ◽  
Dependent Inhibition

Pyrrole-imidazole (PI) polyamides are novel gene silencers that strongly bind the promoter region of target genes in a sequence-specific manner to inhibit gene transcription. We developed a PI polyamide targeting human TGF-b1 (hTGF-b1). To develop PI polyamide targeting hTGF-b1 (Polyamide) as a practical medicine for progressive renal diseases, we examined the effects of Polyamide in two common marmoset models of nephropathy.We performed lead optimization of PI polyamides targeting hTGF-b1 by the dose-dependent inhibition of the PMA-stimulated expression of TGF-b1 mRNA in marmoset fibroblasts. Marmosets were housed with a 0.05% NaCl and magnesium diet and treated with cyclosporine A (CsA; 37.5 mg/kg/day, 8 weeks) to establish chronic nephropathy. Marmosets with nephropathy were treated with Polyamide (1 mg/kg/week, 4 weeks). We also established a unilateral urethral obstruction(UUO) model and examined the effects of Polyamide (1 mg/kg/week, 4 times) in marmosets.Histologically, the renal medulla from CsA-treated marmosets showed cast formation and interstitial fibrosis in the renal medulla. Immunohistochemistry showed strong staining of Polyamide in the renal medulla from CsA-treated marmosets.Polyamidetreatment (1 mg/kg/week, 4 times) reduced hTGF-b1 staining and urinary protein excretion in CsA-treated marmosets. Polyamide reduced the glomerular injury score (GIS) and tubulointerstitial injury score (TIS) in UUO kidneys from marmosets. Polyamide significantly suppressed the hTGF-b1 and Snail mRNA expressionin UUO kidneys from marmosets.PI polyamide effectively improved CsA- and UUO-associated nephropathy, indicating its potential application in the prevention of renal fibrosis in progressive renal diseases.

Interstitial renal disease

2018 ◽  
Author(s):  
William G. Herrington ◽  
Aron Chakera ◽  
Christopher A. O’Callaghan
Keyword(s):  
Renal Disease ◽  
Interstitial Nephritis ◽  
Tubulointerstitial Nephritis ◽  
Interstitial Fibrosis ◽  
Acute Interstitial Nephritis ◽  
Renal Diseases ◽  
Interstitial Tissue ◽  
Renal Tubules ◽  
Early Disease ◽  
Tubular Atrophy

Tubulointerstitial renal diseases affect the renal tubules and/or the supporting interstitial tissue around them. The glomeruli are typically spared in early disease. Acute interstitial nephritis is characterized by an inflammatory infiltrate (often containing eosinophils). Chronic tubulointerstitial nephritis (TIN) is characterized by extensive tubular atrophy and interstitial fibrosis. The processes are clinically distinct but a prolonged acute interstitial nephritis will develop into chronic disease. This chapter looks at the etiology of interstitial renal disease, as well as its symptoms and clinical features, demographics, complications, diagnosis, and treatment.

Cytokines and L-arginine in renal injury and repair

1994 ◽  
Vol 267 (2) ◽  
pp. F197-F207 ◽  
Author(s):  
M. Ketteler ◽  
W. A. Border ◽  
N. A. Noble
Keyword(s):  
Growth Factor ◽  
Renal Disease ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Interstitial Fibrosis ◽  
Renal Diseases ◽  
Tgf Beta ◽  
Arginine Metabolism

Advances in molecular biology have identified cytokines as mediators of pathophysiological changes in chronic renal disease. Transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of glomerular and interstitial fibrosis, whereas platelet-derived growth factor (PDGF) is involved in proliferative changes in chronic progressive renal diseases. Tumor necrosis factor-alpha and interleukins are expressed in experimental models of renal disease and are causes of inflammation and cell migration. Cytokines act by many different mechanisms, and one target of their action may be L-arginine metabolism. Since the discovery of the effector molecule nitric oxide (NO), generated from L-arginine, knowledge of this pathway has increased dramatically. It became evident that the L-arginine/NO pathway is of major importance in the regulation of hemodynamics and neurotransmission, in host defense against intracellular microorganisms, and in immunologic tissue injury. This pathway is induced by proinflammatory cytokines and possibly regulated by TGF-beta and PDGF. L-Arginine is also metabolized to L-ornithine, which can be processed to polyamines or to L-proline. As polyamines are important mediators of cell growth and L-proline is a substrate for collagen synthesis, both pathways, once activated, may be important in repair processes. It is likely that cytokines and L-arginine metabolism are interconnected and that both are involved in the inflammation, tissue repair, and fibrogenesis processes in the kidney. Dietary protein restriction in progressive renal diseases may substantially affect both systems. This review summarizes current knowledge about interactions of cytokines and L-arginine metabolism and the relevance to renal diseases.

THE EFFECTS OF INSULIN-LIKE GROWTH FACTOR-1 AND NERVE GROWTH FACTOR ON DENERVATED MUSCLE ATROPHY

2001 ◽  
Vol 05 (03) ◽  
pp. 193-203 ◽  
Author(s):  
Boonsin Buranapanitkit ◽  
Zhuqing Qu ◽  
Morey M. Moreland ◽  
Alan Geater ◽  
George Somogyi ◽  
...  
Keyword(s):  
Growth Factors ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Muscle Atrophy ◽  
Interstitial Fibrosis ◽  
Insulin Like Growth Factor ◽  
Denervated Muscle ◽  
Nerve Growth ◽  
Wet Weight ◽  
The Mean

The effects of growth factors on denervated muscle atrophy in mouse gastrocnemius muscle were studied by morphometric, physiologic and histologic methods. Fifteen mice were randomized into three groups: intact, denervated-insulin-like growth factor-1-treated (D-IGF-1) and denervated-nerve growth factor-treated (D-NGF). In denervated animals, the left sides were used as a control by injecting balanced salt solution (HBSS), while the right sides were injected with growth factors. The mean wet weight and the mean wet weight/body weight were significantly higher in D-IGF-1 muscles compared to the D-NGF and D-HBSS muscles, but were not different from the muscle of intact controls. Physiologic testing showed that the mean maximal tetanic twitch strength and the mean maximal fast twitch strength were also significantly higher in the D-IGF-1 muscles than in the D-NGF and D-HBSS muscles. Mean time-to-peak was significantly only decreased in the D-NGF muscles. Histological studies found that the mean percentage of type 2 fiber was significantly higher in D-NGF muscles. The types I and II mean diameters in the D-IGF-1 muscles were larger than in the D-NGF and D-HBSS muscles, but all denervated muscles had higher interstitial fibrosis than the intact controls. In conclusion, we show that IGF-1 can effectively retard denervated muscle atrophy by increasing types I and II fibre muscle diameter. However, IGF-1 cannot prevent interstitial fibrosis in the denervated muscle.

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