scholarly journals INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction

2010 ◽  
Vol 299 (6) ◽  
pp. F1486-F1495 ◽  
Author(s):  
Jesse M. Wolstein ◽  
David H. Lee ◽  
Jennine Michaud ◽  
Venessa Buot ◽  
Beth Stefanchik ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Knockout Mice ◽  
Ureteral Obstruction ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Collecting Duct ◽  
Mesenchymal Cell ◽  
Transforming Growth Factor Β ◽  
Unilateral Ureteral Obstruction ◽  
Matrix Deposition

The INK4a proteins p16INK4a and p19ARF regulate cell cycle arrest and senescence. However, the role of these proteins in controlling these processes in the normal kidney and following injury is unknown. We performed unilateral ureteral obstruction (UUO) to induce fibrosis in 2- to 3-mo-old wild-type (WT) C57/B6 and INK4a knockout mice. By quantitative RT-PCR, p16INK4a levels were increased sixfold in WT mice 7 days after UUO and p19ARF remained undetectable. Kidney sections were examined to determine levels and localization of p16INK4a, apoptosis, fibrosis, and senescent cells. INK4a knockout mice displayed mesangial cell proliferation, increased matrix deposition, and myofibroblast differentiation under normal conditions. Following UUO, INK4a knockout mice displayed 10-fold increased tubular and interstitial cell proliferation, 75% decreased collecting duct apoptosis, 2-fold greater collagen and fibronectin deposition, and no cell senescence by senescence-associated β-galactosidase staining compared with WT mice. Both INK4a knockout mesangial cells and kidney lysates from knockout mice following injury showed elevated levels of IL-6 by ELISA compared with WT samples. INK4a knockout epithelial cell cultures displayed increased mesenchymal cell markers when exposed to transforming growth factor-β. These results confirm that p16INK4a controls cell proliferation and matrix production and mitigates fibrosis following injury and suggest that the mechanism involves a role in limiting inflammation and cell proliferation.

scholarly journals UT-A1/A3 knockout mice show reduced fibrosis following unilateral ureteral obstruction

2020 ◽  
Vol 318 (5) ◽  
pp. F1160-F1166
Author(s):  
Fitra Rianto ◽  
Akihiro Kuma ◽  
Carla L. Ellis ◽  
Faten Hassounah ◽  
Eva L. Rodriguez ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Knockout Mice ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Unilateral Ureteral Obstruction

Renal fibrosis is a major contributor to the development and progression of chronic kidney disease. A low-protein diet can reduce the progression of chronic kidney disease and reduce the development of renal fibrosis, although the mechanism is not well understood. Urea reabsorption into the inner medulla is regulated by inner medullary urea transporter (UT)-A1 and UT-A3. Inhibition or knockout of UT-A1/A3 will reduce interstitial urea accumulation, which may be beneficial in reducing renal fibrosis. To test this hypothesis, the effect of unilateral ureteral obstruction (UUO) was compared in wild-type (WT) and UT-A1/A3 knockout mice. UUO causes increased extracellular matrix associated with increases in transforming growth factor-β, vimentin, and α-smooth muscle actin (α-SMA). In WT mice, UUO increased the abundance of three markers of fibrosis: transforming growth factor-β, vimentin, and α-SMA. In contrast, in UT-A1/A3 knockout mice, the increase following UUO was significantly reduced. Consistent with the Western blot results, immunohistochemical staining showed that the levels of vimentin and α-SMA were increased in WT mice with UUO and that the increase was reduced in UT-A1/A3 knockout mice with UUO. Masson’s trichrome staining showed increased collagen in WT mice with UUO, which was reduced in UT-A1/A3 knockout mice with UUO. We conclude that reduced UT activity reduces the severity of renal fibrosis following UUO.

scholarly journals Deficiency of mPGES-1 exacerbates renal fibrosis and inflammation in mice with unilateral ureteral obstruction

2017 ◽  
Vol 312 (1) ◽  
pp. F121-F133 ◽  
Author(s):  
Renfei Luo ◽  
Yutaka Kakizoe ◽  
Feifei Wang ◽  
Xiang Fan ◽  
Shan Hu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Collecting Duct ◽  
Unilateral Ureteral Obstruction ◽  
Prostaglandin E ◽  
Expression Levels ◽  
Collagen Iii ◽  
Tgf Β1

Microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that converts prostaglandin H2 to prostaglandin E2 (PGE2), plays an important role in a variety of inflammatory diseases. We investigated the contribution of mPGES-1 to renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) for 7 days using wild-type (WT) and mPGES-1 knockout (KO) mice. UUO induced increased mRNA and protein expression of mPGES-1 and cyclooxygenase-2 in WT mice. UUO was associated with increased renal PGE2 content and upregulated PGE2 receptor (EP) 4 expression in obstructed kidneys of both WT and mPGES-1 KO mice; EP4 expression levels were higher in KO mice with UUO than those in WT mice. Protein expression of NLRP3 inflammasome components ASC and interleukin-1β was significantly increased in obstructed kidneys of KO mice compared with that in WT mice. mRNA expression levels of fibronectin, collagen III, and transforming growth factor-β1 (TGF-β1) were significantly higher in obstructed kidneys of KO mice than that in WT mice. In KO mice, protein expression of fibronectin and collagen III was markedly increased in obstructed kidneys compared with WT mice, which was associated with increased phosphorylation of protein kinase B (AKT). EP4 agonist CAY10598 attenuated increased expression of collagen I and fibronectin induced by TGF-β1 in inner medullary collecting duct 3 cells. Moreover, CAY10598 prevented the activation of NLRP3 inflammasomes induced by angiotensin II in human proximal tubule cells (HK2). In conclusion, these findings suggested that mPGES-1 exerts a potentially protective effect against renal fibrosis and inflammation induced by UUO in mice.

scholarly journals Inhibition of Yes-Associated Protein by Verteporfin Ameliorates Unilateral Ureteral Obstruction-Induced Renal Tubulointerstitial Inflammation and Fibrosis

2020 ◽  
Vol 21 (21) ◽  
pp. 8184
Author(s):  
Jixiu Jin ◽  
Tian Wang ◽  
Woong Park ◽  
Wenjia Li ◽  
Won Kim ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ureteral Obstruction ◽  
Transforming Growth Factor ◽  
Unilateral Ureteral Obstruction ◽  
Age Related Macular Degeneration ◽  
Smad Signaling ◽  
Matrix Deposition ◽  
Smad Signaling Pathway ◽  
Tgf Β1 ◽  
Tubulointerstitial Inflammation

Yes-associated protein (YAP) activation after acute ischemic kidney injury might be related to interstitial fibrosis and impaired renal tubular regeneration. Verteporfin (VP) is a photosensitizer used in photodynamic therapy to treat age-related macular degeneration. In cancer cells, VP inhibits TEA domain family member (TEAD)-YAP interactions without light stimulation. The protective role of VP in unilateral ureteral obstruction (UUO)-induced renal fibrosis and related mechanisms remains unclear. In this study, we investigate the protective effects of VP on UUO-induced renal tubulointerstitial inflammation and fibrosis and its regulation of the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We find that VP decreased the UUO-induced increase in tubular injury, inflammation, and extracellular matrix deposition in mice. VP also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells by modulating Smad2 and Smad3 phosphorylation. Therefore, YAP inhibition might have beneficial effects on UUO-induced tubulointerstitial inflammation and fibrosis by regulating the TGF-β1/Smad signaling pathway.

scholarly journals Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis

2012 ◽  
Vol 303 (12) ◽  
pp. L1046-L1056 ◽  
Author(s):  
Payal K. Naik ◽  
Paul D. Bozyk ◽  
J. Kelley Bentley ◽  
Antonia P. Popova ◽  
Carolyn M. Birch ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Mesenchymal Cell ◽  
Transforming Growth Factor Β ◽  
Chimeric Mouse ◽  
Wild Type ◽  
Matrix Deposition ◽  
Inflammatory Phase ◽  
Potential Biomarker

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective therapeutics. Periostin has been reported to be elevated in IPF patients relative to controls, but its sources and mechanisms of action remain unclear. We confirm excess periostin in lungs of IPF patients and show that IPF fibroblasts produce periostin. Blood was obtained from 54 IPF patients (all but 1 with 48 wk of follow-up). We show that periostin levels predict clinical progression at 48 wk (hazard ratio = 1.47, 95% confidence interval = 1.03–2.10, P < 0.05). Monocytes and fibrocytes are sources of periostin in circulation in IPF patients. Previous studies suggest that periostin may regulate the inflammatory phase of bleomycin-induced lung injury, but periostin effects during the fibroproliferative phase of the disease are unknown. Wild-type and periostin-deficient (periostin−/−) mice were anesthetized and challenged with bleomycin. Wild-type mice were injected with bleomycin and then treated with OC-20 Ab (which blocks periostin and integrin interactions) or control Ab during the fibroproliferative phase of disease, and fibrosis and survival were assessed. Periostin expression was upregulated quickly after treatment with bleomycin and remained elevated. Periostin−/− mice were protected from bleomycin-induced fibrosis. Instillation of OC-20 during the fibroproliferative phase improved survival and limited collagen deposition. Chimeric mouse studies suggest that hematopoietic and structural sources of periostin contribute to lung fibrogenesis. Periostin was upregulated by transforming growth factor-β in lung mesenchymal cells, and periostin promoted extracellular matrix deposition, mesenchymal cell proliferation, and wound closure. Thus periostin plays a vital role in late stages of pulmonary fibrosis and is a potential biomarker for disease progression and a target for therapeutic intervention.

scholarly journals Inactivation of MAP3K7 in FOXD1-expressing cells results in loss of mesangial PDGFRΒ and juvenile kidney scarring

2018 ◽  
Vol 315 (2) ◽  
pp. F336-F344 ◽  
Author(s):  
Michele J. Karolak ◽  
Justin A. Guay ◽  
Leif Oxburgh
Keyword(s):  
Growth Factor ◽  
Kidney Development ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Renal Scarring ◽  
Transforming Growth Factor Β ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Matrix Deposition ◽  
Jnk Activation

Transforming growth factor-β (TGFβ) plays a central role in renal scarring, controlling extracellular matrix deposition by interstitial cells and mesangial cells. TGFβ signals through Smad and mitogen-activated protein kinase (MAPK) pathways. To understand the role of MAPK in interstitial and mesangial cells, we genetically inactivated TGFβ-activated kinase-1 ( Map3k7) using Foxd1+/cre. Embryonic kidney development was unperturbed in mutants, but spontaneous scarring of the kidney ensued during the first postnatal week, with retention of embryonic nephrogenic rests and accumulation of collagen IV in the mesangium. MAPK signaling in the mesangium of mutant mice was skewed, with depressed p38 but elevated c-Jun NH2-terminal kinase (JNK) activation at postnatal day 3. Despite normal expression of platelet-derived growth factor receptor-β (PDGFRβ) in the mesangium of mutants at birth, expression was lost concomitantly with the increase in JNK activation, and studies in isolated mesangial cells revealed that JNK negatively regulates Pdgfrβ. In summary, we show that MAP3K7 balances MAPK signaling in mesangial cells, suppressing postnatal JNK activation. We propose that the balance of MAPK signaling is essential for appropriate postnatal regulation of mesangial PDGFRβ expression.

scholarly journals Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction

2000 ◽  
Vol 58 (6) ◽  
pp. 2301-2313 ◽  
Author(s):  
Akira Miyajima ◽  
Jie Chen ◽  
Cathy Lawrence ◽  
Steve Ledbetter ◽  
Robert A. Soslow ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ureteral Obstruction ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Unilateral Ureteral Obstruction
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