The Cytokine TWEAK Modulates Renal Tubulointerstitial Inflammation

Abstract

TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily of cytokines. In addition to binding and activating the fibroblast growth factor-inducible 14 receptor, TWEAK may regulate apoptosis, proliferation, and inflammation; however, the role of this system in kidney injury is unknown. In vitro, it was found that TWEAK induced the sustained activation of NF-B in a murine tubular epithelial cell line (MCT). NF-B activation was associated with degradation of IB-␣; translocation of RelA to the nucleus; and increased mRNA and protein expression of monocyte chemoattractant protein-1, RANTES, and IL-6. Similarly, in vivo, the systemic administration of TWEAK induced renal NF-B activation, chemokine and IL-6 expression, and interstitial inflammation in mice. Parthenolide, which prevents IB-␣ degradation, inhibited TWEAK-induced NF-B activation and prevented the aforementioned changes in vitro and in vivo. After folic acid-induced acute kidney injury, fibroblast growth factor-inducible 14 expression increased in mouse tubular epithelium. Neutralization of TWEAK decreased the expression of chemokines in tubular cells and reduced interstitial inflammation. In conclusion, TWEAK has NF-B-dependent proinflammatory effects on tubular epithelial cells in vitro and in vivo. Moreover, blockade of TWEAK reduces tubular chemokine expression and macrophage infiltration, suggesting that TWEAK modulates acute kidney injury by regulating the inflammatory response.

Combined Therapy with Renin-Angiotensin System and Calcium Channel Blockers in Type 2 Diabetic Hypertensive Patients with Proteinuria

“…TWEAK has been recently implicated in the development of vascular and renal damage (30 -33), being expressed in endothelial and vascular smooth muscle cells, macrophages, and tubular and glomerular cells (31,34). The binding of TWEAK to its receptor Fn14 increases the inflammatory response associated with atherosclerotic plaque development and renal lesions (32,35). Unexpectedly, lower plasma sTWEAK has been reported in subjects with subclinical atherosclerosis, diabetic subjects, CKD patients (18 -20,36), and in this study.…”

Soluble TWEAK Plasma Levels as a Novel Biomarker of Endothelial Function in Patients with Chronic Kidney Disease

“…A pathologic role of TWEAK has been demonstrated in animal models of kidney injury (32,33). In this regard, TWEAK is expressed in several tissues, but the expression of its receptor, Fn14, is relatively low in the kidney (33) and undetectable in the arterial wall (34).…”

“…A pathologic role of TWEAK has been demonstrated in animal models of kidney injury (32,33). In this regard, TWEAK is expressed in several tissues, but the expression of its receptor, Fn14, is relatively low in the kidney (33) and undetectable in the arterial wall (34). Under pathologic conditions, Fn14 expression is increased, and cells, including vascular cells, could be sensitized to TWEAK, leading to injurious actions such as apoptosis and production of proinflammatory mediators (33,34).…”

“…In this regard, TWEAK is expressed in several tissues, but the expression of its receptor, Fn14, is relatively low in the kidney (33) and undetectable in the arterial wall (34). Under pathologic conditions, Fn14 expression is increased, and cells, including vascular cells, could be sensitized to TWEAK, leading to injurious actions such as apoptosis and production of proinflammatory mediators (33,34). In such scenario, unknown mechanisms may lead to low TWEAK concentrations to try unsuccessfully to limit tissue injury: Low levels of sTWEAK in patients with CKD may be a compensatory mechanism to protect from the consequences of Fn14 activation (9).…”

HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II

“…Real-time PCR reactions were performed on an ABI Prism 7500 sequence detection PCR system (Applied Biosystems) according to the manufacturer's protocol using the DeltaDelta Ct method. 35 Expression levels are given as ratios to GAPDH. Pre-developed primer and probe assays (PDAR) were obtained for human GAPDH and HSPB1 from Applied Biosystems.…”