Current perspectives on congenital obstructive nephropathy

Ingraham, Susan E.; McHugh, Kirk M.

doi:10.1007/s00467-011-1799-8

Cited by 26 publications

(23 citation statements)

References 93 publications

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“…This variability parallels that seen in humans with obstructive uropathy [1]. In this study, we utilized this variability to evaluate the global transcriptomes of mgb −/− versus control kidneys at varying grades of hydronephrosis.…”

Section: Introductionmentioning

confidence: 89%

“…Congenital obstructive nephropathy (CON) is a leading cause of chronic kidney disease (CKD) and end stage renal disease (ESRD) in children, particularly in boys with prune belly syndrome and posterior urethral valves [1]. The best available biomarker of residual renal function in children with CON is serum creatinine, even though it does not permit physicians to reliably predict which children with obstruction will develop significant CKD [2], [3].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy

et al. 2013

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Congenital obstructive nephropathy is a common cause of chronic kidney disease and a leading indication for renal transplant in children. The cellular and molecular responses of the kidney to congenital obstruction are incompletely characterized. In this study, we evaluated global transcription in kidneys with graded hydronephrosis in the megabladder (mgb −/−) mouse to better understand the pathophysiology of congenital obstructive nephropathy. Three primary pathways associated with kidney remodeling/repair were induced in mgb −/− kidneys independent of the degree of hydronephrosis. These pathways included retinoid signaling, steroid hormone metabolism, and renal response to injury. Urothelial proliferation and the expression of genes with roles in the integrity and maintenance of the renal urothelium were selectively increased in mgb −/− kidneys. Ngal/Lcn2, a marker of acute kidney injury, was elevated in 36% of kidneys with higher grades of hydronephrosis. Evaluation of Ngalhigh versus Ngallow kidneys identified the expression of several novel candidate markers of renal injury. This study indicates that the development of progressive hydronephrosis in mgb −/− mice results in renal adaptation that includes significant changes in the morphology and potential functionality of the renal urothelium. These observations will permit the development of novel biomarkers and therapeutic approaches to progressive renal injury in the context of congenital obstruction.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy

et al. 2013

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“…and molecular pathways (Supplemental Table 5.) associated mainly with the immune homeostasis, which confirms that developmental abnormalities trigger chronic renal inflammation leading to the excessive deposition of ECM components and consequent renal fibrosis [22]. …”

Section: Discussionmentioning

confidence: 99%

“…The severity of congenital developmental anomalies of the urinary tract can vary from the subclinical mild or temporary stenosis to complete obstruction. While mild stenosis do not lead to serious clinical consequences sever urinary tract obstruction results in CON [21, 22]. The high morbidity and mortality rate of pediatric patients with CON and the limitations of currently available treatment options emphasize the need to better understand the underlying mechanisms [23].…”

Section: Discussionmentioning

confidence: 99%

Microarray Analysis Reveals Increased Expression of Matrix Metalloproteases and Cytokines of Interleukin-20 Subfamily in the Kidneys of Neonate Rats Underwent Unilateral Ureteral Obstruction: A Potential Role of IL-24 in the Regulation of Inflammation and Tissue Remodeling

Pap¹,

Sziksz²,

Kiss

et al. 2017

Kidney Blood Press Res

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Background/Aims: Congenital obstructive nephropathy (CON) is the main cause of pediatric chronic kidney diseases leading to renal fibrosis. High morbidity and limited treatment opportunities of CON urge the better understanding of the underlying molecular mechanisms. Methods: To identify the differentially expressed genes, microarray analysis was performed on the kidney samples of neonatal rats underwent unilateral ureteral obstruction (UUO). Microarray results were then validated by real-time RT-PCR and bioinformatics analysis was carried out to identify the relevant genes, functional groups and pathways involved in the pathomechanism of CON. Renal expression of matrix metalloproteinase (MMP)-12 and interleukin (IL)-24 were evaluated by real-time RT-PCR, flow cytometry and immunohistochemical analysis. Effect of the main profibrotic factors on the expression of MMP-12 and IL-24 was investigated on HK-2 and HEK-293 cell lines. Finally, the effect of IL-24 treatment on the expression of pro-inflammatory cytokines and MMPs were tested in vitro. Results: Microarray analysis revealed 880 transcripts showing >2.0-fold change following UUO, enriched mainly in immune response related processes. The most up-regulated genes were MMPs and members of IL-20 cytokine subfamily, including MMP-3, MMP-7, MMP-12, IL-19 and IL-24. We found that while TGF-β treatment inhibits the expression of MMP-12 and IL-24, H₂O₂ or PDGF-B treatment induce the epithelial expression of MMP-12. We demonstrated that IL-24 treatment decreases the expression of IL-6 and MMP-3 in the renal epithelial cells. Conclusions: This study provides an extensive view of UUO induced changes in the gene expression profile of the developing kidney and describes novel molecules, which may play significant role in the pathomechanism of CON.

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“…It is the common end result of a wide range of diseases and processes that cause permanent damage and scarring to the kidney. Congenital obstructive nephropathy (CON), a leading cause of pediatric CKD, is a complex disease process characterized by pathological changes in kidney development and function resulting from restriction of antegrade urine flow beginning in utero (1, 2). Pre- or post-natal surgical interventions may alter the rate of decline in renal function but in many patients CKD progression is inevitable (3).…”

Section: Introductionmentioning

confidence: 99%

Renal epithelial miR-205 expression correlates with disease severity in a mouse model of congenital obstructive nephropathy

Wilhide

Feller

et al. 2016

Pediatr Res

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Background Congenital obstructive nephropathy (CON) is a leading cause of pediatric chronic kidney disease (CKD). Despite optimal surgical and medical care, there is a high rate of CKD progression. Better understanding of molecular and cellular changes is needed to facilitate development of improved biomarkers and novel therapeutic approaches in CON. Methods The megabladder (mgb) mouse is an animal model of CKD with impaired bladder emptying, hydronephrosis, and progressive renal injury. In this study, we characterize a particular microRNA, miR-205, whose expression changes with the degree of hydronephrosis in the mgb-/- kidney. Results Expression of miR-205 is progressively increased in the adult mgb-/-mouse with worsening severity of hydronephrosis. miR-205 expression is correlated with altered expression of cytokeratins and uroplakins, which are markers of cellular differentiation in urothelium. We describe the spatial pattern of miR-205 expression, including increased expression in renal urothelium and novel miR-205 expression in medullary collecting duct epithelium in the congenitally obstructed kidney. Conclusion miR-205 is increased with severity of congenital obstructive nephropathy and CKD in the mgb-/- mouse, and may regulate urothelial differentiation.

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Current perspectives on congenital obstructive nephropathy

Cited by 26 publications

References 93 publications

Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy

Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy

Microarray Analysis Reveals Increased Expression of Matrix Metalloproteases and Cytokines of Interleukin-20 Subfamily in the Kidneys of Neonate Rats Underwent Unilateral Ureteral Obstruction: A Potential Role of IL-24 in the Regulation of Inflammation and Tissue Remodeling

Renal epithelial miR-205 expression correlates with disease severity in a mouse model of congenital obstructive nephropathy

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