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 Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-β signaling in chronic kidney disease

2016 ◽  
Vol 89 (2) ◽  
pp. 327-341 ◽  
Author(s):  
Jun Morinaga ◽  
Tsuyoshi Kadomatsu ◽  
Keishi Miyata ◽  
Motoyoshi Endo ◽  
Kazutoyo Terada ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β

scholarly journals NLRP3 Deficiency Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in a Mouse Unilateral Ureteral Obstruction Model of Chronic Kidney Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Honglei Guo ◽  
Xiao Bi ◽  
Ping Zhou ◽  
Shijian Zhu ◽  
Wei Ding
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Tubulointerstitial Fibrosis ◽  
Mitochondrial Morphology ◽  
Glomerular Injury ◽  
Matrix Deposition

Background and Aims. The nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) inflammasome has been implicated in the pathogenesis of chronic kidney disease (CKD); however, its exact role in glomerular injury and tubulointerstitial fibrosis is still undefined. The present study was performed to identify the function of NLRP3 in modulating renal injury and fibrosis and the potential involvement of mitochondrial dysfunction in the murine unilateral ureteral obstruction (UUO) model of CKD. Methods. Employing wild-type (WT) and NLRP3−/− mice with or without UUO, we evaluated renal structure, tissue injury, and mitochondrial ultrastructure, as well as expression of some vital molecules involved in the progression of fibrosis, apoptosis, inflammation, and mitochondrial dysfunction. Results. The severe glomerular injury and tubulointerstitial fibrosis induced in WT mice by UUO was markedly attenuated in NLRP3−/− mice as evidenced by blockade of extracellular matrix deposition, decreased cell apoptosis, and phenotypic alterations. Moreover, NLRP3 deletion reversed UUO-induced impairment of mitochondrial morphology and function. Conclusions. NLRP3 deletion ameliorates mitochondrial dysfunction and alleviates renal fibrosis in a murine UUO model of CKD.

scholarly journals P0852PERICYTE-SPECIFIC MANIPULATION OF HYPOXIA-INDUCIBLE FACTORS REGULATES ERYTHROPOIESIS WITHOUT AGGRAVATING RENAL FIBROSIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Pei-Zhen Cai ◽  
SZU-YU PAN ◽  
SHUEI-LIONG LIN
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Animal Models ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Mrna Level ◽  
Hypoxia Inducible Factor ◽  
Unilateral Ureteral Obstruction ◽  
Hypoxia Inducible Factors ◽  
Picrosirius Red

Abstract Background and Aims Stabilizers of hypoxia-inducible factor (HIF) have been shown to be effective on treatment of anemia in patients with chronic kidney disease (CKD). Increased erythropoietin (EPO) production and enhanced erythropoiesis are known to be the major mechanisms responsible for the treatment effects. However, the effect of HIF stabilization on renal fibrosis is controversial. We created animal models characterized by CKD and pericyte-specific stabilization of HIF to examine the effects of HIF on renal fibrosis and erythropoiesis. Method Gli1CreERT2/+;Egln1F/F, Gli1CreERT2/+;VhlF/F, and Gli1CreERT2/+;Hif1aF/F;Hif2aF/F mice were generated to study the effects of pericyte-specific overexpression or knockout of Hif. Unilateral ureteral obstruction (UUO) was used to induce CKD. The severity of fibrosis was determined by Picrosirius red stain and Col1a1 mRNA level in the kidney. Results Pericyte-specific stabilization of HIF resulted in increased serum EPO level, augmented splenic erythropoiesis, and polycythemia, while the severity of renal fibrosis was not affected. In line with these findings, pericyte-specific knockout of Hif1a or Hif2a did not result in significant change of renal fibrosis. Conclusion Our study endorses the neutral effects of pericyte-specific HIF stabilization on renal fibrosis.

scholarly journals SREBP inhibition ameliorates renal injury after unilateral ureteral obstruction

2016 ◽  
Vol 311 (3) ◽  
pp. F614-F625 ◽  
Author(s):  
Maria Mustafa ◽  
Tony N. Wang ◽  
Xing Chen ◽  
Bo Gao ◽  
Joan C. Krepinsky
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Ureteral Obstruction ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Fibrotic Process ◽  
Atubular Glomeruli ◽  
Tgf Β1

Tubulointerstitial fibrosis is a major feature associated with declining kidney function in chronic kidney disease of diverse etiology. No effective means as yet exists to prevent the progression of fibrosis. We have shown that the transcription factor sterol-regulatory element-binding protein 1 (SREBP-1) is an important mediator of the profibrotic response to transforming growth factor-β (TGF-β) and angiotensin II, both key cytokines in the fibrotic process. Here, we examined the role of SREBP in renal interstitial fibrosis in the unilateral ureteral obstruction (UUO) model. The two isoforms of SREBP (-1 and -2) were activated by 3 days after UUO, with SREBP-1 showing a more sustained activation to 21 days. We then examined whether SREBP1/2 inhibition with the small-molecule inhibitor fatostatin could attenuate fibrosis after 14 days of UUO. SREBP activation was confirmed to be inhibited by fatostatin. Treatment decreased interstitial fibrosis, TGF-β signaling, and upregulation of α-smooth muscle actin (SMA), a marker of fibroblast activation. Fatostatin also attenuated inflammatory cell infiltrate and apoptosis. Associated with this, fatostatin preserved proximal tubular mass. The significant increase in atubular glomeruli observed after UUO, known to correlate with irreversible renal functional decline, was also decreased by treatment. In cultured primary fibroblasts, TGF-β1 induced the activation of SREBP-1 and -2. Fatostatin blocked TGF-β1-induced α-SMA and matrix protein upregulation. The inhibition of SREBP is thus a potential novel therapeutic target in the treatment of fibrosis in chronic kidney disease.

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 Chronic kidney disease induced in mice by reversible unilateral ureteral obstruction is dependent on genetic background

2010 ◽  
Vol 298 (4) ◽  
pp. F1024-F1032 ◽  
Author(s):  
Tipu S. Puri ◽  
Mohammed I. Shakaib ◽  
Anthony Chang ◽  
Liby Mathew ◽  
Oladunni Olayinka ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Injury ◽  
Ureteral Obstruction ◽  
Genetic Background ◽  
Renal Fibrosis ◽  
Genetic Basis ◽  
Cellular Responses ◽  
Unilateral Ureteral Obstruction ◽  
Number Of Factors

Chronic kidney disease (CKD) begins with renal injury; the progression thereafter depends upon a number of factors, including genetic background. Unilateral ureteral obstruction (UUO) is a well-described model of renal fibrosis and as such is considered a model of CKD. We used an improved reversible unilateral ureteral obstruction (rUUO) model in mice to study the strain dependence of development of CKD after obstruction-mediated injury. C57BL/6 mice developed CKD after reversal of three or more days of ureteral obstruction as assessed by blood urea nitrogen (BUN) measurements (>40 mg/dl). In contrast, BALB/c mice were resistant to CKD with up to 10 days ureteral obstruction. During rUUO, C57BL/6 mice exhibited pronounced inflammatory and intrinsic proliferative cellular responses, disruption of renal architecture, and ultimately fibrosis. By comparison, BALB/c mice had more controlled and measured extrinsic and intrinsic responses to injury with a return to normal within several weeks after release of ureteral obstruction. Our findings provide a model that allows investigation of the genetic basis of events during recovery from injury that contribute to the development of CKD.

scholarly journals Role of Transcription Factors and Growth Factors in Renal Fibrosis in Felines with Kidney Dysfunction

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1532-1532
Author(s):  
Kiran Panickar ◽  
Selena Tavener ◽  
Dennis Jewell
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Nutritional Therapy ◽  
Kidney Dysfunction ◽  
Funding Sources ◽  
Stone Formers ◽  
Potential Therapeutic Role

Abstract Objectives Renal fibrosis, a key feature of progressive chronic kidney dysfunction, is characterized by an excessive deposition of extracellular matrix proteins following injury. It is generally the result of sustained glomerular or tubular injury induced by several factors including pro-inflammatory proteins and oxidative stress. We investigated changes in gene expression that could contribute to renal fibrosis in cats with kidney disease or calcium oxalate stone formers (CaOx) at necropsy Methods At the time of death the circulating levels of creatinine, SDMA, as well as blood urea nitrogen, all markers of kidney decline in cats, were significantly higher in cats with renal disease (n = 11) or CaOx (n = 12) when compared to controls (n = 19). Results Using RNAseq in renal cortex tissue, we found a significant decrease in Krüppel-like factor 15 (KLF15), a zinc-finger transcription factor in cats with kidney disease (–1.99 fold, P < 0.001) and CaOx (–1.89, P < 0.001) when compared to controls. Given that KLF15 can attenuate fibrosis by inhibiting the actions of TGF-β, a key regulator of fibrosis, our results indicate that a lower level of KLF15 in kidney disease and CaOx may contribute to renal fibrosis. Consistent with this, there was an increase in all three forms of transforming growth factor-β (TGF-β1, TGF-β2, and TGF-β3), a potent initiator of renal fibrosis, in both groups compared to controls. There was also a significant increase in the expression of BMP-1, a growth factor belonging to the TGF-β superfamily and pro-fibrotic, in cats with kidney disease (2.48 fold) and stone formers (1.72 fold), compared to controls (both P < 0.01). Further, BMP-7, an endogenous inhibitor of TGF-β signaling in fibrosis and whose potential therapeutic role in treating CKD and reversing fibrosis has been documented, was modestly decreased in both groups (both less than 1.5 fold) compared to controls. A decrease was also seen in CRIM 1, a protein associated with podocyte filtration function and whose reduction is associated with fibrosis, in both groups Conclusions Our data show evidence of renal fibrosis markers that could have contributed to a progressive decline in kidney function. In summary, a nutritional therapy to slow the progression of kidney dysfunction may benefit from the inclusion of dietary ingredients that attenuate renal fibrosis in cats. Funding Sources Funded by Hills PNC, Inc.

TNF-α neutralization ameliorates obstruction-induced renal fibrosis and dysfunction

2007 ◽  
Vol 292 (4) ◽  
pp. R1456-R1464 ◽  
Author(s):  
K. K. Meldrum ◽  
R. Misseri ◽  
P. Metcalfe ◽  
C. A. Dinarello ◽  
K. L. Hile ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Western Blot ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Unilateral Ureteral Obstruction ◽  
Muscle Actin ◽  
Renal Obstruction ◽  
Tnf Α

Upper urinary tract obstruction results in tubulointerstitial fibrosis and a progressive decline in renal function. Although several inflammatory mediators have been implicated in the pathophysiology of renal obstruction, the contribution of TNF-α to obstruction-induced fibrosis and renal dysfunction has not been thoroughly evaluated. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction vs. sham operation. Rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1) every 84 h. The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were analyzed for TNF-α expression (ELISA), macrophage infiltration (ED-1 staining), transforming growth factor-β1 expression (ELISA, RT-PCR), collagen I and IV activity (Western Blot, immunohistochemistry), α-smooth muscle actin accumulation (immunohistochemistry, Western blot analysis), and angiotensinogen expression (Western blot). In a separate arm, the glomerular filtration rate (inulin clearance) of rats subjected to unilateral ureteral obstruction in the presence of either vehicle or PEG-sTNFR1 was determined. Renal obstruction induced increased tissue TNF-α and transforming growth factor-β1 levels, collagen I and IV activity, interstitial volume, α-smooth muscle actin accumulation, angiotensinogen expression, and renal dysfunction, whereas treatment with PEG-sTNFR1 significantly reduced each of these markers of renal fibrosis. These results demonstrate that TNF-α mediates obstruction-induced renal fibrosis and identify TNF-α neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.

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