scholarly journals Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates Smad2/3

2018 ◽  
Vol 315 (6) ◽  
pp. F1822-F1832 ◽  
Author(s):  
Zhengwei Ma ◽  
Qingqing Wei ◽  
Ming Zhang ◽  
Jian-Kang Chen ◽  
Zheng Dong
Keyword(s):  
Kidney Disease ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Proximal Tubules ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Pathological Feature ◽  
Tubular Injury

Renal fibrosis is a common pathological feature in chronic kidney disease (CKD), including diabetic kidney disease (DKD) and obstructive nephropathy. Multiple microRNAs have been implicated in the pathogenesis of both DKD and obstructive nephropathy, although the overall role of microRNAs in tubular injury and renal fibrosis in CKD is unclear. Dicer (a key RNase III enzyme for microRNA biogenesis) was specifically ablated from kidney proximal tubules in mice via the Cre-lox system to deplete micoRNAs. Proximal tubular Dicer knockout (PT- Dicer KO) mice and wild-type (WT) littermates were subjected to streptozotocin (STZ) treatment to induce DKD or unilateral ureteral obstruction (UUO) to induce obstructive nephropathy. Renal hypertrophy, renal tubular apoptosis, kidney inflammation, and tubulointerstitial fibrosis were examined. Compared with WT mice, PT- Dicer KO mice showed more severe tubular injury and renal inflammation following STZ treatment. These mice also developed higher levels of tubolointerstitial fibrosis. Meanwhile, PT- Dicer KO mice had a significantly higher Smad2/3 expression in kidneys than WT mice (at 6 mo of age) in both control and STZ-treated mice. Similarly, UUO induced more severe renal injury, inflammation, and interstitial fibrosis in PT- Dicer KO mice than WT. Although we did not detect obvious Smad2/3 expression in sham-operated mice (2–3 mo old), significantly more Smad2/3 was induced in obstructed PT- Dicer KO kidneys. These results supported a protective role of Dicer-dependent microRNA synthesis in renal injury and fibrosis development in CKD, specifically in DKD and obstructive nephropathy. Depletion of Dicer and microRNAs may upregulate Smad2/3-related signaling pathway to enhance the progression of CKD.

scholarly journals Apoptosis-Associated Speck-Like Protein Containing a CARD Deletion Ameliorates Unilateral Ureteral Obstruction Induced Renal Fibrosis and Endoplasmic Reticulum Stress in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yao Xu ◽  
Yuqing Liu ◽  
Honglei Guo ◽  
Wei Ding
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Pathological Feature ◽  
Ureter Obstruction ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage

Inflammation might be one of the essential underlying mechanisms of renal fibrosis, which is considered a key pathological feature of end-stage renal disease and is closely associated with proteinuria and decreased renal function. Apoptosis-associated speck-like protein containing a CARD (ASC), identified as the central structure of inflammasome, is involved in the progression of interstitial fibrosis; however, its signal transduction pathways remain unclear. In the present study, we performed unilateral ureter obstruction (UUO) in both wild-type and ASC deletion mice to determine the contribution of ASC to renal fibrosis. Compared with control groups, UUO significantly induced renal fibrosis and collagen deposition, as evidenced by photomicrographs. ASC deletion attenuated renal injury, reduced cell infiltration and the release of inflammatory cytokines, protected against apoptosis, and downregulated the PRKR-like endoplasmic reticulum kinase (PERK) pathway of endoplasmic reticulum (ER) stress. Our data identify a novel role of ASC in the regulation of renal fibrosis and ER stress after UUO, strongly indicating that ASC could serve as an attractive target in the treatment of chronic kidney disease.

Targeted deletion of NADPH-Oxidase Nox4 from proximal tubules is dispensable for diabetic kidney disease development

2020 ◽  
Author(s):  
Vicki Thallas-Bonke ◽  
Sih Min Tan ◽  
Runa S Lindblom ◽  
Matthew Snelson ◽  
Cesare Granata ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Nadph Oxidase ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Proximal Tubules ◽  
Disease Development ◽  
Diabetic Kidney ◽  
Genetic Ablation ◽  
Proximal Tubular

Abstract Background The NADPH oxidase isoform, Nox4, mediates reactive oxygen species (ROS) production and renal fibrosis in diabetic kidney disease at the level of the podocyte. However, the mitochondrial localization of Nox4 and its role as a mitochondrial bioenergetic sensor has recently been reported. Whether Nox4 drives pathology in diabetic kidney disease within the proximal tubular compartment, which is densely packed with mitochondria, is not yet known. Methods We generated a proximal tubular specific Nox4 knockout mouse model by breeding Nox4flox/flox mice with mice expressing Cre recombinase under the control of the Sglt2 promoter. Subsets of Nox4ptKO mice and their Nox4flox/flox littermates were injected with streptozotocin (STZ) to induce diabetes. Mice were followed for 20 weeks and renal injury was assessed. Results Genetic ablation of proximal tubular Nox4 (Nox4ptKO) resulted in no change in renal function and histology. Nox4ptKO mice and Nox4flox/flox littermates injected with STZ exhibited the hallmarks of diabetic kidney disease including hyperfiltration, albuminuria, renal fibrosis and glomerulosclerosis. Surprisingly, diabetes-induced renal injury was not improved in Nox4ptKOSTZ mice compared to Nox4flox/flox STZ mice. Although diabetes conferred ROS overproduction and increased mitochondrial oxygen consumption rate, proximal tubular deletion of Nox4 did not normalize oxidative stress or mitochondrial bioenergetics. Conclusion Taken together, these results demonstrate that genetic deletion of Nox4 from the proximal tubules does not influence diabetic kidney disease development, indicating that Nox4 localization within this highly energetic compartment is dispensable for chronic kidney disease pathogenesis in the setting of diabetes.

scholarly journals Unilateral Ureteral Obstruction as a Model of Kidney Fibrosis and Increasing of Systolic Blood Pressure in Mice

2019 ◽  
Vol 2 (3) ◽  
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Systolic Blood Pressure ◽  
Ureteral Obstruction ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Kidney Fibrosis ◽  
End Stage

Background: Obstructive nephropathy can lead to progressive and permanent loss of kidney function characterized by interstitial inflammation and tubulointerstitial fibrosis. Tubulointerstitial fibrosis presents as the end result of various kidney injuries in general and can cause chronic kidney disease (CKD), which can progress to end-stage kidney disease and hypertension. Objective: This study aimed to determine the effectiveness of unilateral ureteral obstruction (UUO) as a model of renal fibrosis and hypertension. Method: Sixteen male Rattus norvegicus mice (150-200 g) were divided into control groups and UUO by ureteral ligation, eight mice each. The systolic blood pressure (SBP) were measured every seven days. After 30 days the animals were dissected to analyze the changes in renal interstitial fibrosis. Statistical analysis was carried out by unpaired t test or alternative test. Results: There was a significant increase in interstitial fibrosis in the UUO rat group [1% (0% - 5%) vs. 75% (20% - ­90%), p <0.001] and SBP [85.38 ± 1.69 mmHg vs 144.75 ± 4.27 mmHg, p <0.001]. Conclusion: UUO can be used as a model of fibrosis and hypertension, which can be used as the basis for the development of anti-fibrotic and anti-hypertensive drugs.

scholarly journals BMPER Ameliorates Renal Fibrosis by Inhibiting Tubular Dedifferentiation and Fibroblast Activation

2021 ◽  
Vol 9 ◽  
Author(s):  
Ting Xie ◽  
Zunen Xia ◽  
Wei Wang ◽  
Xiangjun Zhou ◽  
Changgeng Xu
Keyword(s):  
Kidney Disease ◽  
Renal Fibrosis ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
Tubulointerstitial Fibrosis ◽  
Tubular Damage ◽  
Mesenchymal Transition ◽  
Fibroblast Activation ◽  
Tgf Β1 ◽  
E Cadherin

Tubulointerstitial fibrosis is both a pathological manifestation of chronic kidney disease and a driving force for the progression of kidney disease. A previous study has shown that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) is involved in lung fibrogenesis. However, the role of BMPER in renal fibrosis remains unknown. In the present study, the expression of BMPER was examined by real-time PCR, Western blot and immunohistochemical staining. The in vitro effects of BMPER on tubular dedifferentiation and fibroblast activation were analyzed in cultured HK-2 and NRK-49F cells. The in vivo effects of BMPER were dissected in unilateral ureteral obstruction (UUO) mice by delivery of BMPER gene via systemic administration of plasmid vector. We reported that the expression of BMPER decreased in the kidneys of UUO mice and HK-2 cells. TGF-β1 increased inhibitor of differentiation-1 (Id-1) and induced epithelial mesenchymal transition in HK-2 cells, and knockdown of BMPER aggravated Id-1 up-regulation, E-cadherin loss, and tubular dedifferentiation. On the contrary, exogenous BMPER inhibited Id-1 up-regulation, prevented E-cadherin loss and tubular dedifferentiation after TGF-β1 exposure. In addition, exogenous BMPER suppressed fibroblast activation by hindering Erk1/2 phosphorylation. Knockdown of low-density lipoprotein receptor-related protein 1 abolished the inhibitory effect of BMPER on Erk1/2 phosphorylation and fibroblast activation. Moreover, delivery of BMPER gene improved renal tubular damage and interstitial fibrosis in UUO mice. Therefore, BMPER inhibits TGF-β1-induced tubular dedifferentiation and fibroblast activation and may hold therapeutic potential for tubulointerstitial fibrosis.

scholarly journals Opposite role of CD44-standard and CD44-variant-3 in tubular injury and development of renal fibrosis during chronic obstructive nephropathy

2014 ◽  
Vol 86 (3) ◽  
pp. 558-569 ◽  
Author(s):  
Elena Rampanelli ◽  
Kasper M.A. Rouschop ◽  
Nike Claessen ◽  
Gwendoline J.D. Teske ◽  
Steven T. Pals ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Obstructive Nephropathy ◽  
Chronic Obstructive ◽  
Tubular Injury ◽  
Cd44 Variant

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.

Obstructive nephropathy and renal fibrosis

2002 ◽  
Vol 283 (5) ◽  
pp. F861-F875 ◽  
Author(s):  
Saulo Klahr ◽  
Jeremiah Morrissey
Keyword(s):  
Renal Disease ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Rodent Model ◽  
Renal Diseases ◽  
Obstructive Nephropathy ◽  
Therapeutic Approaches ◽  
Cellular Events ◽  
The Impact ◽  
Made In

Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.

Silymarin Regulates Tgf-β1/Smad3 Signaling Pathway and Improves Renal Tubular Interstitial Fibrosis Caused by Obstructive Nephropathy

2021 ◽  
Vol 19 (4) ◽  
pp. 508-513
Author(s):  
Jinhao Wu ◽  
Chao Huang ◽  
Gang Kan ◽  
Hanyu Xiao ◽  
Xiaoping Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Therapeutic Drugs ◽  
Renal Tubulointerstitial Fibrosis ◽  
Liver And Kidney ◽  
Renal Tubular ◽  
Antioxidant Effects ◽  
Tgf Β1

Obstructive nephropathy often leads to renal tubulointerstitial fibrosis. Understanding of the pathogenesis of renal tubulointerstitial fibrosis caused by obstructive nephropathy is crucial to the development of effective therapeutic drugs to improve the prognosis of the patients. Silymarin, a polyphenolic flavonoid extracted from plants, has been shown to exhibit antiinflammatory and antioxidant effects ameliorating liver and kidney damage. However, the effect of silymarin on renal fibrosis in obstructive nephropathy remains to be explored. In this study, we found silymarin improved interstitial fibrosis and apoptosis induced by TGF-β1 and ameliorated oxidative damage. Our data further confirmed that silymarin regulates the TGF-β1/ Smad3 signaling pathway, and therefore improves renal tubular interstitial fibrosis caused by obstructive nephropathy.

scholarly journals Quantification of TGF-β1 mRNA along rat nephron in obstructive nephropathy

2001 ◽  
Vol 281 (3) ◽  
pp. F513-F521 ◽  
Author(s):  
Kyoichi Fukuda ◽  
Koji Yoshitomi ◽  
Taihei Yanagida ◽  
Masanori Tokumoto ◽  
Hideki Hirakata
Keyword(s):  
In Situ Hybridization ◽  
Mrna Expression ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Proximal Tubules ◽  
Obstructive Nephropathy ◽  
Renal Tubules ◽  
Rt Pcr ◽  
Tgf Β1

Unilateral ureteral obstruction (UUO) leads to interstitial fibrosis of the obstructed kidney, and transforming growth factor-β1 (TGF-β1) is thought to play an important role in this process. Although increased TGF-β1 mRNA expression in the obstructed kidney has been demonstrated, the source of the increased TGF-β1 remains to be elucidated. To determine the precise localization of TGF-β1 in the obstructed kidney, we examined TGF-β1 mRNA expression using in situ hybridization and competitive RT-PCR in rats with UUO. In situ hybridization demonstrated that TGF-β1 mRNA expression was preferentially increased in tubular epithelial cells and to a lesser degree in infiltrating macrophages in obstructed kidneys. Quantitative analysis using competitive RT-PCR in microdissected nephron segments revealed that levels of TGF-β1 mRNA in obstructed kidneys relative to control kidneys increased significantly in proximal tubules, thick ascending limbs of Henle, and distal convoluted tubules, whereas those in glomeruli and collecting ducts did not change significantly. Of the tubular segments, the proximal tubules appeared to predominantly contribute to increased TGF-β1 mRNA. Our findings suggest that renal tubules, particularly proximal tubules, are the main contributors to increased TGF-β1 mRNA expression in obstructed kidneys and to the subsequent interstitial fibrosis.

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