Background and Aims: Identification of new biomarkers and drug targets for diabetic nephropathy (DN) is required for the development of more effective therapy. In this study, we investigated the role of SIK2 in protecting against renal tubular injury.
Methods: Diabetes was induced in C57BL/6 mice by streptozotocin (STZ) injection. Inhibitor ARN-3236 was administered 4 weeks after STZ injection 6 weeks, and metabolic indices and renal function were assessed. The apoptosis of HK2 cells was detected by flow cytometric analysis. The transcriptome sequencing was performed after SIK2 overexpression.
Results: Salt inducible kinase 2 (SIK2) expression was obviously decreased in the diseased kidneys from humans and mice, especially in the tubules. In vivo, downregulation of SIK2 with specific inhibitor ARN3236 accelerates tubular mitochondrial dysfunction, endoplasmic reticulum (ER) stress and apoptosis in STZ mice. In tubular epithelial cells, SIK2 overexpression attenuates thapsigargin-induced ER stress and apoptosis, whereas SIK2 knockdown aggravates apoptosis. Mechanistically, SIK2 overexpression upregulates HSP70 expression by phosphorylating HSF1, and then inhibits ER stress.
Conclusions: The newly identified SIK2/HSF1/HSP70 axis clarified the molecular mechanism of tubular epithelial cells apoptosis, indicating that SIK2 might be a novel target for therapeutic prevention of renal tubular injury.
X. Liao: None. B. Liu: None. H. Zheng: None.
