TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Abstract

Background: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to end-stage kidney disease. Macrophage recruitment and interstitial inflammation have been shown to promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. Methods: In order to evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. Results: Meta-analysis of published animal models data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, while TWEAK was significantly high in urine and cystic fluid from ADPKD patients. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-MAPK signaling, decreased NF-κB pathway activation, slight reduction of fibrosis and apoptosis, and an indirect decrease of macrophage recruitment. Conclusions: This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.

The TWEAK/Fn14/CD163 axis—implications for metabolic disease

“…TWEAK also increases proliferation in renal cells through activating the mitogen-activated protein kinases ERK and p38, the phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway and NF-κB [ 34 ]. Anti-TWEAK monoclonal antibodies inhibit this proliferation through reduction in the expression of MAPK and NF-κB signalling as well as reducing AKT and p38 levels in autosomal dominant polycystic kidney disease preclinical models [ 35 , 36 ].…”

“…CD163 has been recognised as an atherosclerotic plaque modulator due to its anti-inflammatory and anti-atherogenic abilities [ 89 , 90 ]. It is, however, worth noting that numerous diseases such as acute kidney injury, autosomal dominant polycystic kidney disease and rheumatoid arthritis display upregulation of both TWEAK and Fn14 [ 36 , 91 – 93 ]…”

Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

“…Using the same orthologous model of ADPKD ( Pkd1 cond/cond ;Tam-Cre ) [ 18 , 19 ], we investigated whether this window of renal development corresponded in time with a similar window of hepatic development. To draw a direct comparison with our previous studies [ 37 ], mice were induced with tamoxifen to inactivate the Pkd1 gene at postnatal days 14 (p14) and 12 (p12) and sacrificed at the age of 30 days (p30). Interestingly, we observed a cystic phenotype at both time points with a different degree of disease (mild and severe), suggesting that the kidney and liver have independent cystic developmental windows ( Figure 1 a), and/or possible different timings and progression of disease.…”

Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

“…TWEAK is a TNF superfamily cytokine is associated with increased response to inflammation and cell proliferation. Anti-TWEAK antibodies significantly decreased cyst growth in polycystic mice [ 97 ].…”