Publications > Valino-Rivas et al

Trends Mol Med. 2019, 25, 341 PubMed 30926358

NIK as a Druggable Mediator of Tissue Injury.

Lara Valino-Rivas¹, Juan Jose Vaquero², David Sucunza², Sara Gutierrez², Ana B Sanz¹, Manuel Fresno³, Alberto Ortiz^1, 4, a, Maria Dolores Sanchez-Nino^1, 4, a

1. Department of Nephrology and Hypertension, Instituto de Investigacion Sanitaria (IIS) Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid (UAM), Red de Investigacion Renal (REDINREN), and Fundacion Renal Inigo Alvarez de Toledo (FRIAT), Madrid, Spain.  2. Departamento de Quimica Organica y Quimica Inorganica, Universidad de Alcala and REDINREN, Madrid, Spain.  3. Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas de la UAM, Madrid, Spain.  4. These authors contributed equally. Electronic address:.

a. aortiz@fjd.es  a. mdsanchez@fjd.es

Keywords: *MAP3K14; *NIK; *TWEAK; *acute kidney injury; *apoptosis; *autoimmunity; *cell death; *chronic kidney disease; *cirrhosis; *diabetes; *epigenetic; *esteatohepatitis; *hepatitis; *inflammation; *mantle lymphoma; *myeloid leukemia; *osteoporosis; *sarcopenia; *verteporfin

Abstract

NF-kappaB-inducing kinase (NIK, MAP3K14) is best known as the apical kinase that triggers non-canonical NF-kappaB activation and by its role in the immune system. Recent data indicate a role for NIK expressed by non-lymphoid cells in cancer, kidney disease, liver injury, glucose homeostasis, osteosarcopenia, vascular calcification, hematopoiesis, and endothelial function. The spectrum of NIK-associated disease now ranges from immunodeficiency (when NIK is defective) to autoimmunity, cancer, sterile inflammation, fibrosis, and metabolic disease when NIK is overactive. The development of novel small-molecule NIK inhibitors has paved the way to test NIK targeting to treat disease in vivo, and may eventually lead to NIK targeting in the clinic. In addition, NIK activators are being explored for specific conditions such as myeloid leukemia.

Publications > article

Nefrologia 2019, 39, 568 PubMed 31196660

MAP3K kinases and kidney injury.

Leticia Cuarental, David Sucunza, Lara Valino-Rivas, Beatriz Fernandez-Fernandez, Ana Belen Sanz, Alberto Ortiz, Juan Jose Vaquero, Maria Dolores Sanchez-Nino

Palabras clave: *ASK1; *Acute kidney injury; *Diabetic kidney disease; *Enfermedad renal cronica; *Enfermedad renal diabetica; *Kidney; *MAP3K kinases; *MAP3K quinasas; *MAP3K14; *NF-kappaB; *NIK; *Rinon; *Selonsertib; *TWEAK

Resumen

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexplored.