Role of the renin-angiotensin system on the parathyroid hormone-related protein overexpression induced by nephrotoxic acute renal failure in the rat.
Parathyroid hormone-related protein (PTHrP), a mitogenic factor for renal cells, is overexpressed in acute renal failure (ARF). Recent data support an association between PTHrP and the renin-angiotensin system in the damaged kidney. The effects of angiotensin II (Ang II) inhibitors (quinapril, enalapril, and/or losartan) on PTHrP and the PTH1 receptor (PTH1R) expression in rats with either folic acid (FA)- or gentamicin-induced ARF were analyzed. The decreased renal function and the PTHrP upregulation and PTH1R downregulation induced by the nephrotoxins were inhibited by the Ang II blockers. In tubuloepithelial cells NRK-52E, the rapid (10 min) increase in PTHrP mRNA by FA, associated with a perinuclear relocalization of Ang II/AT1 receptor, was inhibited by losartan but not candesartan, which traps Ang II receptors at the cell surface. Maximal PTHrP protein overexpression by FA (at 24 to 72 h)-or by exogenous Ang II-was abolished by both Ang II antagonists. PTHrP upregulation by FA was preceded by increased extracellular signal-regulated kinase (ERK) phosphorylation and inhibited by the ERK inhibitor PD098059. FA also activated cAMP response element-binding (CREB) protein, and this was prevented by losartan in these cells. Moreover, PTHrP mRNA overexpression by either FA or Ang II occurred in NRK 52E that were transfected with a CREB construct but not the dominant-negative CREB133 construct. These findings demonstrate that the decreased renal function and PTHrP overexpression in nephrotoxin-damaged kidney depends on renin-angiotensin system. In this setting, intracellular Ang II/AT1 receptor recycling seems to be related to PTHrP induction through ERK and CREB activation in tubuloepithelial cells.
Ortega
Arantxa
A
Bone and Mineral Metabolism Laboratory, Fundación Jiménez Díaz UTE, Madrid, Spain.
Rámila
David
D
Izquierdo
Adriana
A
González
Laura
L
Barat
Antonio
A
Gazapo
Rosa
R
Bosch
Ricardo J
RJ
Esbrit
Pedro
P
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004656:Enalapril / Q000494:pharmacology; D005492:Folic Acid / Q000494:pharmacology; D005839:Gentamicins; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D000077583:Quinapril; D051381:Rats; D017208:Rats, Wistar; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D005839:Gentamicins; D044162:Parathyroid Hormone-Related Protein; D044168:Receptor, Parathyroid Hormone, Type 1; D044005:Tetrahydroisoquinolines; D000804:Angiotensin II; D004656:Enalapril; D005492:Folic Acid; D019808:Losartan; D000077583:Quinapril