As one of the vital organs of the human body, the importance of the kidney is self-evident. According to data from the National Health and Medical Commission, it is predicted that by 2040, chronic kidney disease will become the fifth leading cause of death in the world. The incidence of chronic kidney disease in my country is as high as 10.8%, and the number of patients exceeds 100 million. Therefore, there is an urgent need to find treatments for damaged kidney function, and some scientists have focused on restoring the kidney's ability to regenerate.
Recently, scientists from the Duke-NUS School of Medicine, the National Heart Center of Singapore (NHCS) and scientists in Germany have shown for the first time that regenerative therapy to restore damaged kidney function may soon become a reality.
After demonstrating the upregulation of IL11 during acute kidney injury, the researchers induced acute kidney injury in IL11-null mice (KO) and wild-type control mice (WT) and studied signaling effects, partial epithelial-mesenchymal transition ( pEMT) markers and renal morphology and function. It was found that IL11 mRNA and IL11 protein levels were increased in the kidneys of wild-type mice, but not detected in IL11-null mice. 28 days after folic acid (FA)-induced kidney injury, the kidneys of wild-type mice were significantly smaller, lighter, more collagen-rich, and more fibrotic than IL11-null mice, that is, kidney injury more obvious.
Next, the researchers investigated whether a neutralizing IL11 antibody (X203) would protect kidney structure and function after severe acute kidney injury. By biochemical (hydroxyproline assay, HPA) and histological analysis, it was found that the X203 treatment regimen resulted in a dose-dependent decrease in renal collagen. Moreover, anti-TGFβ caused inflammation after renal injury, whereas anti-IL11 did not.
Subsequently, the researchers explored in detail the specific role of IL11 in renal proximal tubular epithelial cells and determined that the findings in mice could be related to humans. At the signaling level, both TGFβ1 and IL11 increased the expression of pERK, pp90RSK, pGSK3β, SNAI1, ZEB and αSMA, and downregulated E-Cadherin, Cyclin D1 and PCNA.
These data demonstrate a general dependence of IL11 on the partial epithelial-mesenchymal transition of human renal proximal tubular epithelial cells by driving the ERK/p90RSK/GSK3β/SNAI1 axis. Briefly, IL11 stimulates epithelial-mesenchymal transition in human renal tubular cells, leading to further fibrosis. X203 and neutralizing IL11RA antibodies inhibited the effects of TGFβ1 on signaling and partial epithelial-mesenchymal transition phenotypes, but not IgG, showing that induction of partial epithelial-mesenchymal transition by TGFβ2 is dependent on IL11 in human renal proximal tubular epithelial cells.
Taking these experiments together, the researchers concluded that neutralizing IL11 antibodies could be used to treat acute kidney injury, treat unilateral ureteral obstruction, and reverse chronic kidney disease. Mechanistically, IL-11 triggers scarring in other organs such as the liver, lungs and heart. Renal fibroblasts are activated by paracrine IL11 activity from renal proximal tubular epithelial cells, and this protein triggers a cascade of molecular processes following kidney injury that lead to inflammation, fibrosis (scarring), and loss of function. Anti-IL11 therapy can reverse renal epithelial-mesenchymal transition. Additionally, loss of IL11RA1 in renal proximal tubular epithelial cells protects against long-term sequelae of acute kidney injury.
By boosting the kidney's intrinsic regenerative capacity, researchers can restore function to damaged kidneys. Anti-IL11 therapy can treat kidney failure, and reverse kidney disease, and has been shown to be safe for long-term use in mice. These discoveries make regenerative medicine a significant step forward in disease treatment.