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1.
Cell Stress Chaperones ; 26(6): 973-987, 2021 11.
Article in English | MEDLINE | ID: mdl-34671941

ABSTRACT

Various molecular and cellular processes are involved in renal fibrosis, such as oxidative stress, inflammation, endothelial cell injury, and apoptosis. Heat shock proteins (HSPs) are implicated in the progression of chronic kidney disease (CKD). Our aim was to evaluate changes in urine and serum HSP levels over time and their relationships with the clinical parameters of CKD in children. In total, 117 children with CKD and 56 healthy children were examined. The CKD group was followed up prospectively for 24 months. Serum and urine HSP27, HSP40, HSP47, HSP60, HSP70, HSP72, and HSP90 levels and serum anti-HSP60 and anti-HSP70 levels were measured by ELISA at baseline, 12 months, and 24 months. The urine levels of all HSPs and the serum levels of HSP40, HSP47, HSP60, HSP70, anti-HSP60, and anti-HSP70 were higher at baseline in the CKD group than in the control group. Over the months, serum HSP47 and HSP60 levels steadily decreased, whereas HSP90 and anti-HSP60 levels steadily increased. Urine HSP levels were elevated in children with CKD; however, with the exception of HSP90, they decreased over time. In conclusion, our study demonstrates that CKD progression is a complicated process that involves HSPs, but they do not predict CKD progression. The protective role of HSPs against CKD may weaken over time, and HSP90 may have a detrimental effect on the disease course.


Subject(s)
Heat-Shock Proteins/blood , Heat-Shock Proteins/urine , Inflammation/diagnosis , Renal Insufficiency, Chronic/diagnosis , Apoptosis/genetics , Chaperonin 60/blood , Chaperonin 60/urine , Child , Child, Preschool , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , HSP27 Heat-Shock Proteins/blood , HSP27 Heat-Shock Proteins/urine , HSP40 Heat-Shock Proteins/blood , HSP40 Heat-Shock Proteins/urine , HSP47 Heat-Shock Proteins/blood , HSP47 Heat-Shock Proteins/urine , HSP70 Heat-Shock Proteins/blood , HSP70 Heat-Shock Proteins/urine , HSP72 Heat-Shock Proteins/blood , HSP72 Heat-Shock Proteins/urine , HSP90 Heat-Shock Proteins/blood , HSP90 Heat-Shock Proteins/urine , Heat-Shock Proteins/genetics , Humans , Inflammation/blood , Inflammation/genetics , Inflammation/urine , Male , Oxidative Stress/genetics , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/pathology , Renal Insufficiency, Chronic/urine
2.
Lab Invest ; 100(7): 945-958, 2020 07.
Article in English | MEDLINE | ID: mdl-32203149

ABSTRACT

Podocyte injury and endoplasmic reticulum (ER) stress have been implicated in the pathogenesis of various glomerular diseases. ERdj3 (DNAJB11) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are ER chaperones lacking the KDEL motif, and may be secreted extracellularly. Since podocytes reside in the urinary space, we examined if podocyte injury is associated with secretion of KDEL-free ER chaperones from these cells into the urine, and if chaperones in the urine reflect ER stress in glomerulonephritis. In cultured podocytes, ER stress increased ERdj3 and MANF intracellularly and in culture medium, whereas GRP94 (KDEL chaperone) increased only intracellularly. ERdj3 and MANF secretion was blocked by the secretory trafficking inhibitor, brefeldin A. Urinary ERdj3 and MANF increased in rats injected with tunicamycin (in the absence of proteinuria). After induction of passive Heymann nephritis (PHN) and puromycin aminonucleoside nephrosis (PAN), there was an increase in glomerular ER stress, and appearance of ERdj3 and MANF in the urine, coinciding with the onset of proteinuria. Rats with PHN were treated with the chemical chaperone, 4-phenyl butyrate (PBA), starting at the time of disease induction, or after disease was established. In both protocols, 4-PBA reduced proteinuria and urinary ER chaperone secretion, compared with PHN rats treated with saline (control). In conclusion, urinary ERdj3 and MANF reflect glomerular ER stress. 4-PBA protected against complement-mediated podocyte injury and the therapeutic response could be monitored by urinary ERdj3 and MANF.


Subject(s)
Endoplasmic Reticulum Stress/physiology , Glomerulonephritis/urine , HSP40 Heat-Shock Proteins/urine , Nerve Growth Factors/urine , Animals , Cells, Cultured , Glomerulonephritis/metabolism , Glomerulonephritis/physiopathology , HSP40 Heat-Shock Proteins/metabolism , Kidney Glomerulus/cytology , Kidney Glomerulus/drug effects , Male , Mice , Nerve Growth Factors/metabolism , Rats , Rats, Sprague-Dawley , Tunicamycin/pharmacology
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