TNF-related weak inducer of apoptosis (TWEAK) promotes kidney fibrosis and Ras-dependent proliferation of cultured renal fibroblast

Abstract

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.

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

“…In another study, absence of tumour necrosis factor-like weak inducer of apoptosis (TWEAK) delayed the accumulation of myofibroblasts and reduced ECM deposition in the UUO mouse model. On the other hand, TWEAK overexpression promoted renal fibrosis in mice without any kidney damage (48). These results showed the fibrotic actions of TWEAK that should be further investigated in order to understand the mechanisms of a chronic persistent kidney injury model such as the UUO model.…”

“…It is important to emphasize that these changes are clearly different from the compensatory changes that occur after reduction of renal mass (42). To study renal fibrosis, induced models (surgical and chemical), spontaneous models, genetic models and in vitro models (29,(43)(44)(45)(46)(47)(48) can be used.…”

“…Cultured renal fibroblast cells can be used to evaluate the effect of tumour necrosis factor superfamily cytokines in the induction of the renal fibrosis process. Ucero and colleagues demonstrated that TWEAK induced inflammatory activity and proliferation in renal fibroblast cells, and this action has an RAS-dependent pro-proliferative and NFĸB-dependent proinflammatory effects (48).…”

Deficiency of Fibroblast Growth Factor-Inducible 14 (Fn14) Preserves the Filtration Barrier and Ameliorates Lupus Nephritis

“…Transient TWEAK/Fn14 activation is implicated in physiologic tissue repair and regeneration; however, excessive or persistent activation drives pathologic tissue responses in contexts of chronic injury and disease and contributes to progressive tissue damage and degeneration, 4,7 thereby suggesting this pathway as a potential target for intervention. Other than its known expression in endothelial cells 8 and fibroblasts, 9 we recently found expression of Fn14 on mesangial cells, podocytes, and tubular cells, whereas functional studies have implicated TWEAK/Fn14 signaling in the pathogenesis of renal disease. [9][10][11] Previously, we showed that TWEAK induces human kidney mesangial cells, tubular cells, and podocytes to express multiple inflammatory mediators, including RANTES, MCP-1, IP-10, ICAM-1, and VCAM-1, thus promoting kidney infiltration of inflammatory cells and stimulating cellular proliferation.…”

“…Other than its known expression in endothelial cells 8 and fibroblasts, 9 we recently found expression of Fn14 on mesangial cells, podocytes, and tubular cells, whereas functional studies have implicated TWEAK/Fn14 signaling in the pathogenesis of renal disease. [9][10][11] Previously, we showed that TWEAK induces human kidney mesangial cells, tubular cells, and podocytes to express multiple inflammatory mediators, including RANTES, MCP-1, IP-10, ICAM-1, and VCAM-1, thus promoting kidney infiltration of inflammatory cells and stimulating cellular proliferation. 12,13 In chronic graft-versus-host disease, mice treated with an anti-TWEAK mAb had significantly diminished proteinuria and decreased kidney expression of proinflammatory cytokines.…”