An emerging role of deubiquitinating enzyme cylindromatosis (CYLD) in the tubulointerstitial inflammation of IgA nephropathy.

Abstract

Immunoglobulin A (IgA) nephropathy is an important cause of end-stage kidney disease (ESKD). Tubulointerstitial inflammation and subsequent fibrosis appear to be a major contributor of the disease progression to ESKD; however, the underlying mechanism is poorly understood. Herein, we report that a unique feature of CYLD expression in kidneys of patients with IgA nephropathy and a CYLD-mediated negative regulation of inflammatory responses in human tubular epithelial cells. Immunochemical staining revealed that CYLD was predominantly expressed in renal tubular epithelial cells in 81% of the patients (37 cases) with proteinuric IgA nephropathy. Patients with positive CYLD had significantly less tubulointerstitial lesions and higher estimated glomerular filtration rate (eGFR) levels when compared with those negative. Logistic regression analysis indicated that eGFR was a predictor for the CYLD expression. In cultured human tubular epithelial HK-2 cells, tumor necrosis factor-alpha (TNFalpha) up-regulated CYLD expression. Adenoviral knockdown of CYLD did not affect albumin-, hydrogen peroxide (H(2)O(2))-, tunicamycin- or thapsigargin-induced cell death; however, it enhanced TNFalpha-induced expression of intracellular adhesion molecule (ICAM)-1 as well as activation of c-Jun N-terminal kinase (JNK). Moreover, monocyte adhesion to the TNFalpha-inflamed HK-2 cells was significantly increased by the CYLD shRNA approach. Taken together, our results suggest that CYLD negatively regulates tubulointertitial inflammatory responses via suppressing activation of JNK in tubular epithelial cells, putatively attenuating the progressive tubulointerstitial lesions in IgA nephropathy.

• Authors: Tai-Gen Cui, Tomonaga Ichikawa, Ming Yang, Xiaoyu Dong, Jinqing Li, Taixing Cui
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 390 Issue 2 Pg. 307-12 (Dec 11 2009) ISSN: 1090-2104 [Electronic] United States
• PMID: 19800320 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Necrosis Factor-alpha
• Tumor Suppressor Proteins
• MAP Kinase Kinase 4
• CYLD protein, human
• Deubiquitinating Enzyme CYLD

Topics

• Cell Adhesion
• Deubiquitinating Enzyme CYLD
• Gene Knockdown Techniques
• Glomerulonephritis, IGA (enzymology, genetics, pathology)
• Humans
• Kidney Tubules (enzymology, pathology)
• MAP Kinase Kinase 4 (metabolism)
• Monocytes (enzymology, physiology)
• Nephritis, Interstitial (enzymology, genetics, pathology)
• Signal Transduction
• Tumor Necrosis Factor-alpha (metabolism)
• Tumor Suppressor Proteins (genetics, physiology)