Molecular mechanisms of endoplasmic reticulum stress-mediated acute kidney injury in juvenile rats and the protective role of mesencephalic astrocyte-derived neurotrophic factor

Abstract Objectives This study examined the role of endoplasmic reticulum stress in pediatric acute kidney injury and the therapeutic effect of midbrain astrocyte-derived neurotrophic factor. Methods Two-week-old Sprague-Dawley rats were divided into: Sham, ischemia-reperfusion injury-induced acute kidney injury (AKI), mesencephalic astrocyte-derived neurotrophic factor (MANF)-treated, tauroursodeoxycholic acid (TUDCA)-treated. Analyses were conducted 24 h post-treatment. Serum creatinine, cystatin C, Albumin, MANF levels were measured, cytokine concentrations in serum and renal tissues were determined using a Luminex assay. Histopathology was assessed via light and electron microscopy. Western blotting and RT-qPCR analyzed markers for oxidative stress, apoptosis, endoplasmic reticulum (ER) stress, and autophagy. HK-2 cells underwent hypoxia/reoxygenation (H/R) to simulate AKI and were treated with MANF or TUDCA. Results AKI rats had increased serum creatinine, cystatin C, and inflammatory cytokines, along with significant renal damage, and showed loose and swollen ER structures, reduced cell proliferation, and elevated levels of IRE1, PERK, ATF6, CHOP, LC3-II/I, KIM-1, TLR4, JNK, and NF-κB. MANF treatment reduced these biomarkers and protein levels, improved ER structure and cell proliferation, alleviated oxidative stress, apoptosis, ER stress, and inhibited JNK/TLR4/NF-κB signaling. In HK-2 cells, MANF reduced ER stress and inflammation post-H/R exposure. Conclusions MANF treatment alleviates ER stress, oxidative stress, apoptosis, and inflammation in pediatric AKI, improving renal function and morphology.