scholarly journals Altered myogenic vasoconstriction and regulation of whole kidney blood flow in the ASIC2 knockout mouse

2015 ◽  
Vol 308 (4) ◽  
pp. F339-F348 ◽  
Author(s):  
Kimberly P. Gannon ◽  
Susan E. McKey ◽  
David E. Stec ◽  
Heather A. Drummond
Keyword(s):  
Blood Flow ◽  
Protein Interactions ◽  
Renal Injury ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Protective Role ◽  
Organ Injury ◽  
Loss Of Function ◽  
Kidney Blood Flow ◽  
Myogenic Regulation

Previous studies from our laboratory have suggested that degenerin proteins contribute to myogenic constriction, a mechanism of blood flow regulation and protection against pressure-dependent organ injury, in renal vessels. The goal of the present study was to determine the importance of one family member, acid-sensing ion channel 2 (ASIC2), in myogenic constriction of renal interlobar arteries, myogenic regulation of whole kidney blood flow, renal injury, and blood pressure using ASIC2+/+, ASIC2+/−, and ASIC2−/− mice. Myogenic constriction in renal interlobar arteries was impaired in ASIC2+/− and ASIC2−/− mice, whereas constriction to KCl/phenylephrine was unchanged. Correction of whole kidney renal vascular resistance (RVR) during the first 5 s after a 10- to 20-mmHg step increase in perfusion pressure, a timeframe associated with myogenic-mediated correction of RVR, was slowed (4.2 ± 0.9, 0.3 ± 0.7, and 2.4 ± 0.3 resistance units/s in ASIC2+/+, ASIC2+/−, and ASIC2−/− mice). Although modest reductions in function were observed in ASIC2−/− mice, greater reductions were observed in ASIC2+/− mice, which may be explained by protein-protein interactions of ASIC2 with other degenerins. Isolated glomeruli from ASIC2+/− and ASIC2−/− mice had modest alterations in the expression of inflammation and injury markers (transforming growth factor-β, mouse anti-target of antiproliferative antibody-1, and nephrin), whereas ASIC2+/− mice had an increase in the remodeling marker collagen type III. Consistent with a more severe loss of function, mean arterial pressure was increased in ASIC2+/− mice (131 ± 3 mmHg) but not in ASIC2−/− mice (122 ± 3 vs. 117 ± 2 mmHg in ASIC2+/+ mice). These results suggest that ASIC2 contributes to transduction of the renal myogenic response and are consistent with the protective role of myogenic constriction against renal injury and hypertension.

scholarly journals Renal inflammation and elevated blood pressure in a mouse model of reduced β-ENaC

2011 ◽  
Vol 301 (2) ◽  
pp. F443-F449 ◽  
Author(s):  
Heather A. Drummond ◽  
Samira C. Grifoni ◽  
Ahmed Abu-Zaid ◽  
Monette Gousset ◽  
Rumbidayzi Chiposi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Renal Injury ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Renal Inflammation ◽  
Arterial Blood ◽  
Collagen Iii ◽  
Renal Changes ◽  
Kidney Blood Flow

Previous studies suggest β-epithelial Na+ channel protein (β-ENaC) may mediate myogenic constriction, a mechanism of blood flow autoregulation. A recent study demonstrated that mice with reduced levels of β-ENaC (β-ENaC m/m) have delayed correction of whole kidney blood flow responses, suggesting defective myogenic autoregulatory capacity. Reduced renal autoregulatory capacity is linked to renal inflammation, injury, and hypertension. However, it is unknown whether β-ENaC m/m mice have any complications associated with reductions in autoregulatory capacity such as renal inflammation, injury, or hypertension. To determine whether the previously observed altered autoregulatory control was associated with indicators of renal injury, we evaluated β-ENaC m/m mice for signs of renal inflammation and tissue remodeling using marker expression. We found that inflammatory and remodeling markers, such as IL-1β, IL-6, TNF-α, collagen III and transforming growth factor-β, were significantly upregulated in β-ENaC m/m mice. To determine whether renal changes were associated with changes in long-term control of blood pressure, we used radiotelemetry and found that 5-day mean arterial blood pressure (MAP) was significantly elevated in β-ENaC m/m (120 ± 3 vs. 105 ± 2 mmHg, P = 0.016). Our findings suggest loss of β-ENaC is associated with early signs of renal injury and increased MAP.

Abnormal mouse lung alveolarization caused by Smad3 deficiency is a developmental antecedent of centrilobular emphysema

2005 ◽  
Vol 288 (4) ◽  
pp. L683-L691 ◽  
Author(s):  
Hui Chen ◽  
Jianping Sun ◽  
Sue Buckley ◽  
Cheng Chen ◽  
David Warburton ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Morphological Changes ◽  
Mrna Level ◽  
Transforming Growth Factor Β ◽  
Lavage Fluid ◽  
Protective Role ◽  
Mouse Lung ◽  
Regulatory Impact ◽  
Mouse Lung Tissue ◽  
Null Mutant Mice

Transforming growth factor-β (TGF-β) signaling plays an important regulatory role during lung development and remodeling. Smad3 is a major downstream signal transducer in the TGF-β pathway from the cell membrane to the nucleus. In Smad3 null mutant mice, we have observed retarded lung alveolarization from postnatal day 7 to day 28, and subsequently centrilobular emphysema starting from day 28, as determined by morphometric analysis. In addition to the morphological changes, peripheral lung cell proliferation in Smad3 knockout mice was reduced compared with the wild-type control between postnatal days 7 and 28. Expression of tropoelastin at the mRNA level was also dramatically decreased in Smad3 knockout lungs from postnatal day 28 through adulthood. Furthermore, increased matrix metalloproteinase-9 protein expression and activity were detected in the Smad3 knockout mouse lung tissue and the bronchoalveolar lavage fluid at postnatal day 28 when the centrilobular emphysema pathology was just beginning to appear. Therefore, these results indicate that Smad3 not only has a positive regulatory impact on neonatal lung alveolarization but also potentially plays a protective role against the occurrence of centrilobular emphysema later on in life.

scholarly journals Expression and Function of Transforming Growth Factor β in Melioidosis

2012 ◽  
Vol 80 (5) ◽  
pp. 1853-1857 ◽  
Author(s):  
Tassili A. F. Weehuizen ◽  
Catharina W. Wieland ◽  
Gerritje J. W. van der Windt ◽  
Jan-Willem Duitman ◽  
Louis Boon ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Organ Injury ◽  
Antibody Treatment ◽  
Content Type ◽  
Smad2 Phosphorylation ◽  
Distant Organ ◽  
Proinflammatory Role ◽  
And Function

ABSTRACTMelioidosis, caused by the Gram-negative bacteriumBurkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast Asia and northern Australia. An important controller of the immune system is the pleiotropic cytokine transforming growth factor β (TGF-β), of which Smad2 and Smad3 are the major signal transducers. In this study, we aimed to characterize TGF-β expression and function in experimental melioidosis. TGF-β expression was determined in 33 patients with culture-proven infection withB. pseudomalleiand 30 healthy controls. We found that plasma TGF-β concentrations were strongly elevated during melioidosis. In line with this finding, TGF-β expression in C57BL/6 mice intranasally inoculated withB. pseudomalleiwas enhanced as well. To assess the role of TGF-β, we inhibited TGF-β using a selective murine TGF-β antibody. Treatment of mice with anti-TGF-β antibody resulted in decreased lung Smad2 phosphorylation. TGF-β blockade appeared to be protective: mice treated with anti-TGF-β antibody and subsequently infected withB. pseudomalleishowed diminished bacterial loads. Moreover, less distant organ injury was observed in anti-TGF-β treated mice as shown by reduced blood urea nitrogen (BUN) and aspartate transaminase (AST) values. However, anti-TGF-β treatment did not have an effect on survival. In conclusion, TGF-β is upregulated duringB. pseudomalleiinfection and plays a limited but proinflammatory role during experimental melioidosis.

scholarly journals Renoprotective effects of C-peptide in the Dahl salt-sensitive rat

2012 ◽  
Vol 303 (6) ◽  
pp. F893-F899 ◽  
Author(s):  
R. Taylor Sawyer ◽  
Elizabeth R. Flynn ◽  
Zachary M. Hutchens ◽  
Jan M. Williams ◽  
Michael R. Garrett ◽  
...  
Keyword(s):  
Renal Disease ◽  
Protein Expression ◽  
Renal Injury ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Experimental Models ◽  
Tubulointerstitial Fibrosis ◽  
Time Of Death ◽  
Glomerular Permeability ◽  
C Peptide

Previous studies have demonstrated that renoprotective effects of C-peptide in experimental models of diabetes-induced renal disease may be mediated via lowering blood glucose. The present study examined the renoprotective effects of C-peptide in a model of nondiabetic renal disease, the Dahl salt-sensitive (SS/jr) rat. SS/jr rats were placed on a 2% NaCl diet for 2 wk (HS2, resulting in mild to moderate renal injury) or 4 wk (HS4, resulting in advanced renal injury) and then received either vehicle (veh) or C-peptide (Cpep) for additional 4 wk. Urine albumin (UAE) and protein (UPE) excretion rates were measured at baseline (i.e., before initiation of veh or Cpep treatment) and 4 wk later (i.e., at the time of death). Glomerular permeability, indexes of glomerulosclerosis and tubulointerstitial fibrosis, the presence of inflammatory cells, and protein expression of transforming growth factor-β (TGF-β) and podocin were measured at the time of death. In HS2 + veh rats, UAE and UPE increased by 74 and 92%, respectively, from baseline and the time of death. While HS2 + Cpep attenuated this increase in UAE and UPE, HS4 + Cpep had no effect on these parameters. Similarly, HS2 + Cpep reduced glomerular permeability, tubulointerstitial fibrosis, renal inflammation, TGF-β, and podocin protein expression, while HS4 + Cpep had no effect. These studies indicate that C-peptide is renoprotective in nondiabetic experimental models with mild to moderate renal injury.

scholarly journals The evolutionarily conserved deubiquitinase UBH1/UCH-L1 augments DAF7/TGF-β signaling, inhibits dauer larva formation, and enhances lung tumorigenesis

2020 ◽  
Vol 295 (27) ◽  
pp. 9105-9120 ◽  
Author(s):  
Asami Nagata ◽  
Fumiko Itoh ◽  
Ayaka Sasho ◽  
Kaho Sugita ◽  
Riko Suzuki ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
A549 Cells ◽  
Transforming Growth Factor Β ◽  
Human Homolog ◽  
Loss Of Function ◽  
Lung Tumorigenesis ◽  
Smad Signaling ◽  
C Elegans ◽  
Dauer Larva

Modification of the transforming growth factor β (TGF-β) signaling components by (de)ubiquitination is emerging as a key regulatory mechanism that controls cell signaling responses in health and disease. Here, we show that the deubiquitinating enzyme UBH-1 in Caenorhabditis elegans and its human homolog, ubiquitin C-terminal hydrolase-L1 (UCH-L1), stimulate DAF-7/TGF-β signaling, suggesting that this mode of regulation of TGF-β signaling is conserved across animal species. The dauer larva–constitutive C. elegans phenotype caused by defective DAF-7/TGF-β signaling was enhanced and suppressed, respectively, by ubh-1 deletion and overexpression in the loss-of-function genetic backgrounds of daf7, daf-1/TGF-βRI, and daf4/R-SMAD, but not of daf-8/R-SMAD. This suggested that UBH-1 may stimulate DAF-7/TGF-β signaling via DAF-8/R-SMAD. Therefore, we investigated the effect of UCH-L1 on TGF-β signaling via its intracellular effectors, i.e. SMAD2 and SMAD3, in mammalian cells. Overexpression of UCH-L1, but not of UCH-L3 (the other human homolog of UBH1) or of the catalytic mutant UCH-L1C90A, enhanced TGF-β/SMAD-induced transcriptional activity, indicating that the deubiquitination activity of UCH-L1 is indispensable for enhancing TGF-β/SMAD signaling. We also found that UCH-L1 interacts, deubiquitinates, and stabilizes SMAD2 and SMAD3. Under hypoxia, UCH-L1 expression increased and TGF-β/SMAD signaling was potentiated in the A549 human lung adenocarcinoma cell line. Notably, UCH-L1–deficient A549 cells were impaired in tumorigenesis, and, unlike WT UCH-L1, a UCH-L1 variant lacking deubiquitinating activity was unable to restore tumorigenesis in these cells. These results indicate that UCH-L1 activity supports DAF-7/TGF-β signaling and suggest that UCH-L1's deubiquitination activity is a potential therapeutic target for managing lung cancer.

Stomach regional specification requiresHoxa5-driven mesenchymal-epithelial signaling

Development ◽  
2002 ◽  
Vol 129 (17) ◽  
pp. 4075-4087 ◽  
Author(s):  
Josée Aubin ◽  
Ugo Déry ◽  
Margot Lemieux ◽  
Pierre Chailler ◽  
Lucie Jeannotte
Keyword(s):  
Growth Factor ◽  
Hox Genes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Signaling Molecules ◽  
Loss Of Function ◽  
Expression Of Genes ◽  
Molecular Events ◽  
Genes Encoding ◽  
Fibroblast Growth Factor 10

The genetic control of gut regionalization relies on a hierarchy of molecular events in which the Hox gene family of transcription factors is suspected to be key participant. We have examined the role of Hox genes in gut patterning using the Hoxa5–/– mice as a model. Hoxa5 is expressed in a dynamic fashion in the mesenchymal component of the developing gut. Its loss of function results in gastric enzymatic anomalies in Hoxa5–/– surviving mutants that are due to perturbed cell specification during stomach development. Histological, biochemical and molecular characterization of the mutant stomach phenotype may be compatible with a homeotic transformation of the gastric mucosa. As the loss of mesenchymal Hoxa5 function leads to gastric epithelial defects, Hoxa5 should exert its action by controlling molecules involved in mesenchymal-epithelial signaling. Indeed, in the absence of Hoxa5 function, the expression of genes encoding for signaling molecules such as sonic hedgehog, Indian hedgehog, transforming growth factor β family members and fibroblast growth factor 10, is altered. These findings provide insight into the molecular controls of patterning events of the stomach, supporting the notion that Hoxa5 acts in regionalization and specification of the stomach by setting up the proper domains of expression of signaling molecules.

Antihypertensive effects of chronic anti-TGF-β antibody therapy in Dahl S rats

2002 ◽  
Vol 283 (3) ◽  
pp. R757-R767 ◽  
Author(s):  
Annette J. Dahly ◽  
Kimberly M. Hoagland ◽  
Averia K. Flasch ◽  
Sharda Jha ◽  
Steven R. Ledbetter ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Transforming Growth Factor ◽  
Antibody Therapy ◽  
Transforming Growth Factor Β ◽  
Type Iii Collagen ◽  
Renal Hypertrophy ◽  
Medullary Blood Flow ◽  
Tgf Β1

This study examined the role of transforming growth factor-β (TGF-β) in the development of hypertension and renal disease in 9-wk-old male Dahl salt-sensitive (Dahl S) rats fed an 8% NaCl diet for 3 wk. The rats received an intraperitoneal injection of a control or an anti-TGF-β antibody (anti-TGF-β Ab) every other day for 2 wk. Mean arterial pressure was significantly lower in Dahl S rats treated with anti-TGF-β Ab (177 ± 3 mmHg, n = 12) than in control rats (190 ± 4 mmHg, n = 17). Anti-TGF-β Ab therapy also reduced proteinuria from 226 ± 20 to 154 ± 16 mg/day. Renal blood flow, cortical blood flow, and creatinine clearance were not significantly different in control and treated rats; however, medullary blood flow was threefold higher in the treated rats than in the controls. Despite the reduction in proteinuria, the degree of glomerulosclerosis and renal hypertrophy was similar in control and anti-TGF-β Ab-treated rats. Renal levels of TGF-β1 and -β2, α-actin, type III collagen, and fibronectin mRNA decreased in rats treated with anti-TGF-β Ab. To examine whether an earlier intervention with anti-TGF-β Ab would confer additional renoprotection, these studies were repeated in a group of 6-wk-old Dahl S rats. Anti-TGF-β Ab therapy significantly reduced blood pressure, proteinuria, and the degree of glomerulosclerosis and renal medullary fibrosis in this group of rats. The results indicate that anti-TGF-β Ab therapy reduces blood pressure, proteinuria, and the renal injury associated with hypertension.

Role of the TGF-β/BMP-7/Smad pathways in renal diseases

2012 ◽  
Vol 124 (4) ◽  
pp. 243-254 ◽  
Author(s):  
Xiao-Ming Meng ◽  
Arthur C. K. Chung ◽  
Hui Y. Lan
Keyword(s):  
Renal Injury ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Biological Activities ◽  
Transforming Growth Factor Β ◽  
Renal Diseases ◽  
Ubiquitin E3 Ligase ◽  
Tgf Β1

TGF-β (transforming growth factor-β) and BMP-7 (bone morphogenetic protein-7), two key members in the TGF-β superfamily, play important but diverse roles in CKDs (chronic kidney diseases). Both TGF-β and BMP-7 share similar downstream Smad signalling pathways, but counter-regulate each other to maintain the balance of their biological activities. During renal injury in CKDs, this balance is significantly altered because TGF-β signalling is up-regulated by inducing TGF-β1 and activating Smad3, whereas BMP-7 and its downstream Smad1/5/8 are down-regulated. In the context of renal fibrosis, Smad3 is pathogenic, whereas Smad2 and Smad7 are renoprotective. However, this counter-balancing mechanism is also altered because TGF-β1 induces Smurf2, a ubiquitin E3-ligase, to target Smad7 as well as Smad2 for degradation. Thus overexpression of renal Smad7 restores the balance of TGF-β/Smad signalling and has therapeutic effect on CKDs. Recent studies also found that Smad3 mediated renal fibrosis by up-regulating miR-21 (where miR represents microRNA) and miR-192, but down-regulating miR-29 and miR-200 families. Therefore restoring miR-29/miR-200 or suppressing miR-21/miR-192 is able to treat progressive renal fibrosis. Furthermore, activation of TGF-β/Smad signalling inhibits renal BMP-7 expression and BMP/Smad signalling. On the other hand, overexpression of renal BMP-7 is capable of inhibiting TGF-β/Smad3 signalling and protects the kidney from TGF-β-mediated renal injury. This counter-regulation not only expands our understanding of the causes of renal injury, but also suggests the therapeutic potential by targeting TGF-β/Smad signalling or restoring BMP-7 in CKDs. Taken together, the current understanding of the distinct roles and mechanisms of TGF-β and BMP-7 in CKDs implies that targeting the TGF-β/Smad pathway or restoring BMP-7 signalling may represent novel and effective therapies for CKDs.

scholarly journals Intrarenal Renin–Angiotensin System Involvement in the Pathogenesis of Chronic Progressive Nephropathy—Bridging the Informational Gap Between Disciplines

2019 ◽  
Vol 47 (7) ◽  
pp. 799-816 ◽  
Author(s):  
Leslie A. Obert ◽  
Kendall S. Frazier
Keyword(s):  
Protein Interactions ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Transforming Growth Factor Β ◽  
Critical Pathway ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Age Related ◽  
Using Data

Chronic progressive nephropathy (CPN) is the most commonly encountered spontaneous background finding in laboratory rodents. Various theories on its pathogenesis have been proposed, but there is a paucity of data regarding specific mechanisms or physiologic pathways involved in early CPN development. The current CPN mechanism of action for tumorigenesis is largely based on its associated increase in tubular cell proliferation without regard to preceding subcellular degenerative changes. Combing through the published literature from multiple biology disciplines provided insight into the preceding cellular events. Mechanistic pathways involved in the progressive age-related decline in rodent kidney function and several key inflexion points have been identified. These critical pathway factors were then connected using data from renal models from multiple rodent strains, other species, and mechanistic work in humans to form a cohesive picture of pathways and protein interactions. Abundant data linked similar renal pathologies to local events involving hypoxia (hypoxia-inducible factor 1α), altered intrarenal renin–angiotensin system (RAS), oxidative stress (nitric oxide), and pro-inflammatory pathways (transforming growth factor β), with positive feedback loops and downstream effectors amplifying the injury and promoting scarring. Intrarenal RAS alterations seem to be central to all these events and may be critical to CPN development and progression.

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