FKBP51, AmotL2 and IQGAP1 Involvement in Cilastatin Prevention of Cisplatin-Induced Tubular Nephrotoxicity in Rats
Rebeca González-Fernández,
María Ángeles González-Nicolás,
Manuel Morales,
Julio Ávila,
Alberto Lázaro,
Pablo Martín-Vasallo
Affiliations
Rebeca González-Fernández
Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular and Centro de, Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, Av. Astrofísico Sánchez s/n., 38206 La Laguna, Spain
María Ángeles González-Nicolás
Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
Manuel Morales
Department of Medical Oncology, Nuestra Señora de Candelaria University Hospital, 38010 Santa Cruz de Tenerife, Spain
Julio Ávila
Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular and Centro de, Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, Av. Astrofísico Sánchez s/n., 38206 La Laguna, Spain
Alberto Lázaro
Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
Pablo Martín-Vasallo
Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular and Centro de, Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, Av. Astrofísico Sánchez s/n., 38206 La Laguna, Spain
The immunophilin FKBP51, the angiomotin AmotL2, and the scaffoldin IQGAP1 are overexpressed in many types of cancer, with the highest increase in leucocytes from patients undergoing oxaliplatin chemotherapy. Inflammation is involved in the pathogenesis of nephrotoxicity induced by platinum analogs. Cilastatin prevents renal damage caused by cisplatin. This functional and confocal microscopy study shows the renal focal-segmental expression of TNFα after cisplatin administration in rats, predominantly of tubular localization and mostly prevented by co-administration of cilastatin. FKBP51, AmotL2 and IQGAP1 protein expression increases slightly with cilastatin administration and to a much higher extent with cisplatin, in a cellular- and subcellular-specific manner. Kidney tubule cells expressing FKBP51 show either very low or no expression of TNFα, while cells expressing TNFα have low levels of FKBP51. AmotL2 and TNFα seem to colocalize and their expression is increased in tubular cells. IQGAP1 fluorescence increases with cilastatin, cisplatin and joint cilastatin-cisplatin treatment, and does not correlate with TNFα expression or localization. These data suggest a role for FKBP51, AmotL2 and IQGAP1 in cisplatin toxicity in kidney tubules and in the protective effect of cilastatin through inhibition of dehydropeptidase-I.
