Lin28A Overexpression Triggers Inflammatory Response in Mouse Kidneys

The RNA-binding proteins Lin28A and Lin28B play critical roles in regulating gene expression through distinct mechanisms, including the inhibition of Let-7 microRNA maturation and direct mRNA binding. Predominantly expressed in pluripotent and multipotent stem cells, Lin28A and Lin28B contribute to a variety of biological processes such as development, growth, and tissue regeneration. Dysregulation of Lin28A/B expression is associated with numerous types of tumors. In this study, we demonstrate that overexpression of Lin28A in the mouse nephrons leads to severe inflammation and kidney damage, rather than to tumorigenesis. To investigate the causal relationship between kidney damage and inflammation, we utilized steroid treatment to suppress inflammation. This treatment also ameliorated the kidney damage phenotype, indicating that Lin28A overexpression directly induces inflammation, which in turn leads to kidney damage. Notably, Lin28A overexpression causes inflammation only when expressed in nephrons, but not in the stromal cells of the kidneys, highlighting its cell context-dependent nature. The nephron-specific, Lin28A-induced inflammatory response is distinct from the previously described Lin28B-mediated inflammatory feedback loops, as it is not IL-6 dependent. Instead, it is associated with the rapid upregulation of cytokines such as CXCL1 and CCL2. Overall, this study reveals that the impact of abnormal Lin28A expression is broader than previously understood, demonstrating that Lin28A overexpression also plays a role in inflammatory responses. Furthermore, this transgenic mouse model offers a valuable tool for advancing our understanding of the pathophysiology of acute kidney injury (AKI), where inflammation is a key factor. RNA was extracted form the kidneys of the following samples in triplicate - Lin28A OE inducibale transgenic transgenic mice (Lox-stop-Lox-TetOn-Lin28A;Six2Cre) and control (Lox-stop-Lox-TetOn-Lin28A) upon 1,2,5 weeks of Doxycyline treatment. RNA seq analysis was preformed for each sample