Abstract
The protective effects of brain-derived neurotrophic factor (BDNF) against endoplasmic reticulum (ER) stress in neuronal tissue and endometrial cells have been reported. The aim of this study was to determine whether endogenously produced BDNF protects the kidneys against tunicamycin-induced (Tm) ER stress. Brain-derived neurotrophic factor heterozygous knockout mice (BDNF(+/-)) and their wild-type (WT) littermates were used. The animals were divided into 4 groups: WT, BDNF(+/-), WT+Tm, and BDNF(+/-)+Tm (n = 7 in each group). After 3 days of saline or Tm injection (0.5 mg/kg; intraperitoneally (i.p.)), renal BDNF, glucose-regulated protein 78 (GRP78), and caspase-12 levels as well as serum BDNF concentration were measured with enzyme-linked immunosorbent assay (ELISA). In the kidney sections, hematoxylin & eosin (H&E) staining, GADD153 immunostaining and TUNEL staining were performed. Serum creatinine levels were measured as an indicator of renal function. Circulating and tissue BDNF levels were significantly lower in the BDNF(+/-) and BDNF(+/-)+Tm groups. Renal levels of GRP78 and caspase-12, apoptotic index, and GADD153 staining were significantly higher in the WT+Tm and BDNF(+/-)+Tm groups. However, apoptosis was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.01). Similarly, GADD153 staining was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.05). Tm caused a mild deterioration in the kidney tissue of the WT+Tm group, while general deterioration, pyknotic nuclei and swollen cells were observed in the BDNF(+/-)+Tm group. Serum creatinine concentrations were significantly higher in the WT+Tm (p < 0.05) and BDNF(+/-)+Tm (p < 0.05) groups. This study showed that endogenous BDNF may play a protective role in kidneys against ER stress-induced apoptosis via the suppression of GADD153. As a result, BDNF and related signaling pathways could be considered for therapeutic/protective approaches in kidney disorders.
Highlights
The endoplasmic reticulum (ER) is a multifunctional organelle necessary for the folding and processing of nascent proteins, the synthesis of cholesterol, steroids and other lipids, as well as for calcium storage
Renal levels of glucose-regulated protein 78 (GRP78) and caspase-12, apoptotic index, and GADD153 staining were significantly higher in the with tunicamycin (WT+Tm) and brain-derived neurotrophic factor (BDNF)(+/–)+Tm groups
Tm caused a mild deterioration in the kidney tissue of the WT+Tm group, while general deterioration, pyknotic nuclei and swollen cells were observed in the BDNF(+/–)+Tm group
Summary
The endoplasmic reticulum (ER) is a multifunctional organelle necessary for the folding and processing of nascent proteins, the synthesis of cholesterol, steroids and other lipids, as well as for calcium storage. Activation of UPR pathways first results in the global attenuation of protein synthesis and prevents any further accumulation of unfolded proteins. Upregulation of chaperones such as GRP78 and GRP94, which improve ER folding capacity, and upregulation of the ER-associated degradation system, which activates the degradation of misfolded proteins, are 2 other major adaptive responses.[1,2,3] Despite these defense mechanisms, ER stress can trigger apoptosis, depending on the severity and duration of stress. The protective effects of brain-derived neurotrophic factor (BDNF) against endoplasmic reticulum (ER) stress in neuronal tissue and endometrial cells have been reported
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