Renal response to tunicamycin-induced endoplasmic reticulum stress in BDNF heterozygous mice

Abstract

Background. The protective effects of brain-derived neurotrophic factor (BDNF) against endoplasmic reticulum (ER) stress in neuronal tissue and endometrial cells have been reported.

Objectives. The aim of this study was to determine whether endogenously produced BDNF protects the kidneys against tunicamycin-induced (Tm) ER stress.

Material and methods. 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.

Results. 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.

Conclusions. 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.