Role of the Renin-Angiotensin System on the Parathyroid Hormone–Related Protein Overexpression Induced by Nephrotoxic Acute Renal Failure in the Rat
Arantxa Ortega*,
David Rámila*,
Adriana Izquierdo,
Laura González,
Antonio Barat,
Rosa Gazapo,
Ricardo J. Bosch and
Pedro Esbrit*
* Bone and Mineral Metabolism Laboratory, Pathology Department, and Biochemistry Department, Fundación Jiménez Daz UTE, Madrid; and Laboratory of Renal Physiology and Experimental Nephrology, Department of Physiology, Alcalá University, Alcalá de Henares, Spain
Address correspondence to: Dr. Pedro Esbrit, Laboratorio de Metabolismo Mineral y Óseo, Fundación Jiménez Daz-UTE, Avda. Reyes Católicos 2, 28040 Madrid, Spain. Phone: 34-91-550-4894; Fax: 34-91-549-8075; E-mail:pesbrit{at}fjd.es
Received for publication April 27, 2004.
Accepted for publication January 7, 2005.
Parathyroid hormone–related protein (PTHrP), a mitogenicfactor for renal cells, is overexpressed in acute renal failure(ARF). Recent data support an association between PTHrP andthe renin-angiotensin system in the damaged kidney. The effectsof angiotensin II (Ang II) inhibitors (quinapril, enalapril,and/or losartan) on PTHrP and the PTH1 receptor (PTH1R) expressionin rats with either folic acid (FA)- or gentamicin-induced ARFwere analyzed. The decreased renal function and the PTHrP upregulationand PTH1R downregulation induced by the nephrotoxins were inhibitedby the Ang II blockers. In tubuloepithelial cells NRK-52E, therapid (10 min) increase in PTHrP mRNA by FA, associated witha perinuclear relocalization of Ang II/AT1 receptor, was inhibitedby losartan but not candesartan, which traps Ang II receptorsat the cell surface. Maximal PTHrP protein overexpression byFA (at 24 to 72 h)—or by exogenous Ang II—was abolishedby both Ang II antagonists. PTHrP upregulation by FA was precededby increased extracellular signal-regulated kinase (ERK) phosphorylationand inhibited by the ERK inhibitor PD098059. FA also activatedcAMP response element-binding (CREB) protein, and this was preventedby losartan in these cells. Moreover, PTHrP mRNA overexpressionby either FA or Ang II occurred in NRK 52E that were transfectedwith a CREB construct but not the dominant-negative CREB133construct. These findings demonstrate that the decreased renalfunction and PTHrP overexpression in nephrotoxin-damaged kidneydepends on renin-angiotensin system. In this setting, intracellularAng II/AT1 receptor recycling seems to be related to PTHrP inductionthrough ERK and CREB activation in tubuloepithelial cells.
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az-UTE, Avda. Reyes Católicos 2, 28040 Madrid, Spain. Phone: 34-91-550-4894; Fax: 34-91-549-8075; E-mail:pesbrit{at}fjd.es
