How does Ruibo Bio-IGF-1 protect renal tubular epithelial cells via the ERK/MAPK signaling pathway?

Ruibo Bio--Nature Sub-Journal: How does IGF-1 help patients avoid kidney disease?

Damage to renal tubular epithelial cells can induce acute renal failure and obstructive nephropathy. Insulin-like growth factor-1 (IGF-1) can improve renal damage caused by unilateral ureteral ligation (UOO) in mice, but its underlying mechanism is not fully understood. In June of this year, the research team of Shanghai Jiaotong University Medical College published an article in the Nature journal Scientific Reports. They found that IGF-1 may protect renal tubular epithelial cells through ERK/MAPK signaling pathway when kidney is damaged.

First, let's see how the research team set up the experimental group and the control group: the first group of mice underwent UUO surgery, half of which were intraperitoneally injected with IGF-1 every day, and the remaining saline was used for control; the second group of mice Sham operation was performed and the same treatment as the first group was performed, namely UUO/IGF-1 group, UUO group, sham operation/IGF-1 group, sham operation group.

The design ideas and methods of this experiment are relatively clear and simple, let us explore together.

Knowing the general experimental ideas and methods, let's take a look at the experimental results they have drawn.

IGF-1: I am against UUO

UUO is a mature kidney injury pattern that can cause persistent renal fibrosis. IGF-1 has been shown to improve kidney damage and the renal fibrosis caused by it. The researchers validated this conclusion and explored whether IGF-1 affects UUO-induced apoptosis in renal epithelial cells. UUO-induced renal epithelial cell apoptosis was induced by fluorescence apoptosis assay, and IGF-1 reduced UUO-induced renal epithelial cell apoptosis.

IGF-1: Anti-apoptotic protein Bcl-2, I will help you

Subsequently, the expression of apoptosis-related proteins in the experimental and control mice was examined. In the UUO/IGF-1 group, Bcl-2 was significantly increased at the protein level but not at the mRNA level. This suggests that IGF-1 may increase the anti-apoptotic protein Bcl-2 by modifying the translation of Bcl-2 protein, thereby reducing renal epithelial cell apoptosis in the UUO group.

The dispute between IGF-1 and miR-429

Based on the above conclusions, the investigators hypothesized that IGF-1 can affect Bcl-2 in renal epithelial cells via miRNAs. Through biological information analysis and detection. They found that miR-429 has a binding site at the 3' UTR of Bcl-2, whereas miR-429 levels are significantly reduced in the UUO/IGF-1 mouse kidney epithelial cells.

Next, the investigators transfected miR-429 mimic or antisense into renal epithelial cells and demonstrated that binding of miR-429 to the 3' UTR of Bcl-2 mRNA inhibits Bcl-2 protein by RT-qPCR and luciferase reporter assays. translation. The data indicate that miR-429 does inhibit Bcl-2 protein translation in renal epithelial cells.

IGF-1: miR-429, see I use the ERK1/2 signal path to subdue you

To understand how IGF-1 inhibits miR-429 in UUO mice, they used IGF-1 downstream signaling inhibitors in UUO/IGF-1 cells in vitro to test their effects on Bcl-2. The results showed that inhibition of ERK1/2 signaling by PD98059 (ERK/MAPK-p42/44 inhibitor) not only reduced the effect of IGF-1 on miR-429, but also decreased the activation level of Bcl-2. The data indicate that IGF-1 inhibits miR-429, which is dependent on the ERK/MAPK signaling pathway, to protect renal epithelial cells from renal damage, and that miR-429 inhibition is dependent on Bcl-2 anti-apoptosis.

Prevention of renal epithelial cell apoptosis is the key to protecting kidney function after kidney injury. As a well-known anti-apoptotic gene, Bcl-2 stabilizes mitochondria, blocks the classical apoptotic pathway, and inhibits self-adhesion by binding to Beclin1. In this study, the investigators found that Bcl-2 is controlled by IGF-1 under UUO conditions as a major mechanism of renal epithelial cell resistance to injury and survival, and demonstrated that Bcl-2 is regulated by IGF-1 at the post-transcriptional level. of. In gastric cancer cells and endothelial cells, miR-429 is shown to inhibit Bcl-2 protein translation. This article reports for the first time that IGF-1 regulates miRNA-429 and is regulated by the ERK/MAPK-p42/p44 signaling pathway-dependent manner.

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