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00925njm 22002777a 4500 dc Ucero Herrería, Álvaro Conrado author Benito Martín, Alberto author Fuentes Calvo, Isabel author Santamaria, Beatriz author Blanco González, Julia author López Novoa, José M. author Ruíz Ortega, Marta author Egido, Jesus author Burkly, Linda C. author Martínez Salgado, Carlos author Ortiz, Alberto author 2013-06-06 Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) regulates apoptosis, proliferation and inflammation in renal epithelial cells and plays a role in acute kidney injury. However, there is little information on the chronic effects of TWEAK. We hypothesized that TWEAK may influence renal fibrosis and regulate kidney fibroblast biology, in part, through Ras pathway. We studied a chronic model of experimental unilateral ureteral obstruction in wild type and TWEAK deficient mice, and a murine model of systemic TWEAK overexpression. TWEAK actions were also explored in cultured renal and embryonic fibroblasts. TWEAK and TWEAK receptor expression was increased in the obstructed kidneys. The absence of TWEAK decreased early kidney tubular damage, inflammatory infiltrates and myofibroblast number. TWEAK deficient mice had decreased renal fibrosis 21days after obstruction, as assessed by extracellular matrix staining. In mice without prior underlying kidney disease, systemic overexpression of TWEAK induced kidney inflammation and fibrosis. In cultured fibroblasts, TWEAK induced proliferation through activation of the Ras/ERK pathway. TWEAK also activated nuclear factor κB (NFκB)-dependent inflammatory chemokine production in murine renal fibroblasts. In conclusion, lack of TWEAK reduces renal fibrosis in a model of persistent kidney insult and overexpression of TWEAK led to renal fibrosis. TWEAK actions on renal fibroblasts may contribute to the in vivo observations, as TWEAK promotes inflammatory activity and proliferation in fibroblast cultures. Ucero AC, Benito-Martin A, Fuentes-Calvo I, Santamaria B, Blanco J, Lopez- Novoa JM, Ruiz-Ortega M, Egido J, Burkly LC, Martinez-Salgado C, Ortiz A. TNF- related weak inducer of apoptosis (TWEAK) promotes kidney fibrosis and Ras- dependent proliferation of cultured renal fibroblast. Biochim Biophys Acta. 2013 Oct;1832(10):1744-55 0925-4439 10.1016/j.bbadis.2013.05.032 https://hdl.handle.net/20.500.14352/116737 1879-260X https://doi.org/10.1016/j.bbadis.2013.05.032 23748045 https://www.sciencedirect.com/science/article/pii/S0925443913002032?via%3Dihub https://pubmed.ncbi.nlm.nih.gov/23748045/ TNF-related weak inducer of apoptosis (TWEAK) promotes kidney fibrosis and Ras-dependent proliferation of cultured renal fibroblast