On November 14, 2014, researchers from the Chinese University of Hong Kong, Hong Kong Baptist University, Mount Sinai Icahn School of Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Chongqing Medical University and Southern University of Science and Technology, in the internationally renowned journal The Journal Of Biological Chemistry, published a recent study entitled "Heat shock 70kDa protein 5 (Hspa5) is essential for pronephros formation by mediating retinoic acid signaling", a study that shows that Hspa5, a key to unfolded protein response Regulatory factors play an important role in the formation of the pro-renal, partly mediated by RA signaling during early embryonic development.
The kidney is an important organ that maintains the homeostasis of the environment by filtering, excreting waste and maintaining water and salt balance in the body. In vertebrates, the kidney system develops from three successive developmental forms, the anterior kidney, the middle kidney, and the hind kidney, which originate from the middle and visceral mesoderm during embryonic development. Although there are significant differences between these three forms of anatomy, the nephron is the basic structural and functional unit. The nephron includes three components: the glomerulus, the renal tubules, and the catheter. From the anterior kidney to the posterior kidney, the continuous form becomes more complicated in the number and organization of the nephrons. In higher vertebrates, the posterior kidney functions as a mature kidney, while in amphibians such as Xenopus laevis, the kidney plays a role in the mature kidney and the anterior kidney plays a role in the embryonic period. In vertebrates, the developmental endpoints are different. In zebrafish, frogs, mice, rats, and humans, the molecular mechanisms involved in kidney development are evolutionarily conserved.
Kidney development is a complex multi-step process. It begins in the middle mesoderm of the axon stage. Many signaling pathways, including BMP, Wnt, FGF, Notch, and retinoic acid (RA) signals, are involved in the development of the anterior kidney. These coordinated signaling cascades trigger the expression of a range of transcription factors, including Lhx1, Wt1 and Pax8, which together coordinate the induction of the pro-renal primordium.
The RA signal plays a different role in the development of the pre-renal. In early Xenopus gastrula, treatment with all-trans retinoic acid (atRA) and activin induces the transformation of ectodermal cells into anterior kidney tissue. Inhibition of the RA signal can impair the formation of the anterior kidney.
Heat shock 70kDa protein 5 (Hspa5), also known as binding immunoglobulin (Bip) or glucose-regulated protein 78 (Grp78), belongs to the heat shock protein family, which is involved in protein folding, calcium homeostasis and as endoplasmic reticulum (ER) An important regulator of stress response. It also participates in signal transduction through its role as a receptor or co-receptor that resides on the plasma membrane. However, its function during embryonic development remains elusive.
In this study, the researchers used morpholino antisense oligonucleotides (MO) to knock out Hspa5 activity in Xenopus embryos. In the Hspa5 morphine mutant, the formation of the anterior kidney was strongly inhibited by the reduction of the pro-renal marker genes lhx1, pax2 and atp1b1. In vitro, anterior kidney tissue is induced by treating animal caps with all-trans retinoic acid (atRA) and activin.
However, deletion of Hspa5 in the animal cap blocked the induction of the anterior kidney and reduced the expression of the RA response gene, suggesting that knocking out Hspa5 attenuates the RA signal. Knocking out Hspa5 in animal caps results in decreased expression of lhx1, a transcription factor that is directly regulated by RA signaling, essential for pre-renal specialization. Co-injection of Hspa5MO and lhx1 mRNA partially rescued the Hspa5MO-induced phenotype.
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