Uromodulin deficiency alters tubular injury and interstitial inflammation but not fibrosis in experimental obstructive nephropathy

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.

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Tubular Injury and Dendritic Cell Activation Are Integral Components of Light Chain–Associated Acute Tubulointerstitial Nephritis

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2018-0032-oa ◽

2019 ◽

Vol 143 (10) ◽

pp. 1212-1224 ◽

Cited By ~ 2

Author(s):

Mingyu Cheng ◽

Xin Gu ◽

Elba A. Turbat-Herrera ◽

Guillermo A. Herrera

Keyword(s):

Dendritic Cells ◽

Light Chain ◽

Tubulointerstitial Nephritis ◽

Light Chains ◽

Tubular Injury ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Interstitial Inflammation ◽

Biopsy Specimens ◽

Proximal Tubular

Context.— Light chain–associated acute tubulointerstitial nephritis (LC-ATIN) is a variant of light chain proximal tubulopathy (LCPT). It is characterized by interstitial inflammation with tubulitis and deposition of monoclonal light chains in the tubulointerstitium. LC-ATIN is a rather poorly recognized pattern of LCPT and not much is known about this entity. Objective.— To determine the clinicopathologic features of patients with LC-ATIN and investigate the proximal tubular injury and mechanism of interstitial inflammation in LC-ATIN. Design.— A total of 38 cases of LC-ATIN were identified from the archives of 5043 renal biopsy specimens. In all cases, routine light microscopic examination, immunofluorescence, and electron microscopic examination were performed. In selected cases, immunofluorescent staining of dendritic cells and immunohistochemical staining for 4 tubular injury markers—KIM-1, p53, bcl-2, and Ki-67—were performed. Results.— A characteristic finding in LC-ATIN cases was immunofluorescence staining of monoclonal light chains along tubular basement membranes in linear fashion and inside proximal tubular cells with a granular pattern. No monoclonal light chains were present in glomerular or vascular compartments confirmed with immunofluorescence, electron microscopy, and ultrastructural gold labeling. Ten of 15 LC-ATIN cases (67%) were concurrently positive for the 4 tubular injury markers. Dendritic cells were identified within the tubulointerstitium in the renal biopsy specimens, interacting with surrounding tubules with light-chain deposits and inflammatory cells. Conclusions.— Significant proximal tubular injury occurs associated with LC-ATIN, and the monoclonal light chains accumulated in proximal tubular cells contribute to the injury. Dendritic cells are involved in the pathogenesis of interstitial inflammation in LC-ATIN.

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CCAAT-enhancer binding protein delta (C/EBPδ) attenuates tubular injury and tubulointerstitial fibrogenesis during chronic obstructive nephropathy

Laboratory Investigation ◽

10.1038/labinvest.2013.127 ◽

2013 ◽

Vol 94 (1) ◽

pp. 89-97 ◽

Cited By ~ 6

Author(s):

JanWillem Duitman ◽

Keren S Borensztajn ◽

Willem PC Pulskens ◽

Jaklien C Leemans ◽

Sandrine Florquin ◽

...

Keyword(s):

Binding Protein ◽

Obstructive Nephropathy ◽

Chronic Obstructive ◽

Tubular Injury ◽

Enhancer Binding Protein ◽

Ccaat Enhancer Binding Protein

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Use of xanthine oxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis in unilateral ureteral obstructive nephropathy

Clinical and Experimental Nephrology ◽

10.1007/s10157-012-0609-3 ◽

2012 ◽

Vol 16 (4) ◽

pp. 549-556 ◽

Cited By ~ 54

Author(s):

Hiroki Omori ◽

Noritaka Kawada ◽

Kazunori Inoue ◽

Yoshiyasu Ueda ◽

Ryohei Yamamoto ◽

...

Keyword(s):

Xanthine Oxidase ◽

Oxidase Inhibitor ◽

Obstructive Nephropathy ◽

Xanthine Oxidase Inhibitor ◽

Interstitial Inflammation

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Diagnostic roles of urinary kidney injury molecule 1 and soluble C5b-9 in acute tubulointerstitial nephritis

AJP Renal Physiology ◽

10.1152/ajprenal.00176.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. F584-F592 ◽

Cited By ~ 1

Author(s):

Wen-Ting Zhao ◽

Jun-Wen Huang ◽

Ping-Ping Sun ◽

Tao Su ◽

Jia-Wei Tang ◽

...

Keyword(s):

Tubulointerstitial Nephritis ◽

Kidney Injury ◽

Acute Injury ◽

Tubular Injury ◽

Acute Tubulointerstitial Nephritis ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Interstitial Inflammation ◽

Renal Tubular ◽

Kidney Injury Molecule 1

Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury characterized by inflammatory cells infiltrating in the interstitium. The present study aimed to explore noninvasive biomarkers that might indicate activity of pathological injuries and help direct treatment. Fifty-four patients with clinical-pathologically diagnosed ATIN from January 1, 2014, to June 30, 2016, at Peking University First Hospital were enrolled. Urine samples were collected on the morning of renal biopsy and assessed for urinary kidney injury molecule-1 (KIM-1) and urinary soluble C5b-9 (sC5b-9). Immunofluorescence staining for KIM-1 and C5b-9 was performed in biopsied kidney sections from ATIN cases. The clinical and pathological relevance of the two urinary biomarkers was analyzed. Both urinary KIM-1 and sC5b-9 values were significantly elevated in patients with ATIN compared with healthy controls. The urinary KIM-1 level positively correlated with urinary N-acetyl-β-d-glucosaminidase ( r = 0. 542, P = 0.001) and the pathological tubular injury score ( r = 0.469, P < 0.001), whereas the urinary sC5b-9 level was related to pathological activity scores for tubular injury ( r = 0.413, P = 0.002), interstitial inflammation ( r = 0.388, P = 0.004), and treatment response ( r = 0.564, P < 0.001). Urinary KIM-1 tended to have better diagnostic value for tubular injury than urinary sC5b-9, whereas only urinary sC5b-9 was able to demonstrate severe interstitial inflammation. A combination of urinary KIM-1 and sC5b-9 had an area under the receiver-operating characteristic curve of 0.864 (95% confidence interval: 0.766–0.963, P < 0.001, sensitivity: 75%, specificity: 88%) for acute tissue injury in ATIN. KIM-1 expression was markedly increased in renal tubular cells in both ATIN and acute tubular necrosis conditions, whereas a significant upregulation of C5b-9 was only detected in the tubular cells and interstitial cells in ATIN cases. Urinary KIM-1 is a specific biomarker for renal tubular injury in ATIN, whereas urinary sC5b-9 is valuable in demonstrating severe interstitial inflammation. The combination of these two biomarkers helps identify patients at an acute injury stage and, therefore, might facilitate clinical evaluation and guide immunosuppressive therapy.

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Simultaneous deletion of Bax and Bak is required to prevent apoptosis and interstitial fibrosis in obstructive nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00170.2015 ◽

2015 ◽

Vol 309 (6) ◽

pp. F540-F550 ◽

Cited By ~ 11

Author(s):

Hee-Seong Jang ◽

Babu J. Padanilam

Keyword(s):

Cell Death ◽

Interstitial Fibrosis ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Obstructive Nephropathy ◽

Tubular Injury ◽

Kidney Fibrosis ◽

Cycle Arrest ◽

Proximal Tubular ◽

And Oxidative Stress

Proximal tubular injury and apoptosis are key mediators of the development of kidney fibrosis, a hallmark of chronic kidney disease. However, the molecular mechanism by which tubular apoptotic cell death leads to kidney fibrosis is poorly understood. In the present study, we tested the roles of Bcl-2-associated X (Bax) and Bcl-2 antagonist/killer (Bak), two crucial proteins involved in intrinsic apoptotic cell death, in the progression of kidney fibrosis. Mice with proximal tubule-specific Bax deletion, systemic deletion of Bak, and dual deletion of Bax and Bak were subjected to unilateral ureteral obstruction (UUO). Dual deficiency of Bax and Bak inhibited tubular apoptosis and atrophy. Consistent with decreased tubular injury, dual ablation of Bax and Bak suppressed UUO-induced inflammation and kidney fibrosis with decreased tubular cell cycle arrest, expression of fibrogenic and inflammatory cytokines, and oxidative stress in the kidney. Bax or Bak deficiency was insufficient to prevent apoptosis and all other aforementioned malevolent effects, suggesting compensatory mediation by each other in the respective signaling pathways. These data suggest that dual ablation of Bax and Bak in the kidney is required to prevent UUO-induced tubular apoptosis and the consequent kidney inflammation and fibrosis.

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Disruption of cyclooxygenase type 2 exacerbates apoptosis and renal damage during obstructive nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00253.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. F1035-F1048 ◽

Cited By ~ 14

Author(s):

Line Nilsson ◽

Kirsten Madsen ◽

Søren Krag ◽

Jørgen Frøkiær ◽

Boye L. Jensen ◽

...

Keyword(s):

Oxidative Stress ◽

Antioxidant Enzymes ◽

Heme Oxygenase ◽

Ureteral Obstruction ◽

Obstructive Nephropathy ◽

Heme Oxygenase 1 ◽

Oxidative Stress Markers ◽

Tubular Injury ◽

Stress Markers ◽

Cox 2

Renal oxidative stress is increased in response to ureteral obstruction. In vitro, cyclooxygenase (COX)-2 activity contributes to protection against oxidants. In the present study, we tested the hypothesis that COX-2 activity counters oxidative stress and apoptosis in an in vivo model of obstructive nephropathy. Renal oxidative stress markers, antioxidant enzymes, and markers of tubular injury, tubular dilation, and apoptosis were investigated in COX-2 knockout (COX-2−/−) and wild-type (WT) mice subjected to 3 or 7 days of unilateral ureteral obstruction (UUO). In a separate series, WT sham-operated and UUO mice were treated with a selective COX-2 inhibitor, parecoxib. COX-2 increased in response to UUO; the oxidative stress markers 4-hydroxynonenal and nitrotyrosine protein residues increased in kidney tissue with no genotype difference after UUO, whereas the antioxidant enzymes heme oxygenase-1 and SOD2 displayed higher levels in COX-2−/− mice. Tubular injury was aggravated by COX-2 deletion, as measured by tubular dilatation, an increase in kidney injury molecule-1, cortical caspase-3 content, and apoptosis index. In conclusion, COX-2 is necessary to protect against tubular injury and apoptosis after UUO but not necessary to protect against oxidative stress. COX-2 is not likely to directly regulate antioxidant enzymes heme oxygenase-1 and SOD in the kidney.

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