Angiotensin II increases parathyroid hormone-related protein (PTHrP) and the type 1 PTH/PTHrP receptor in the kidney.
Angiotensin II (AngII) participates in the pathogenesis of kidney damage. Parathyroid hormone (PTH)-related protein (PTHrP), a vasodilator and mitogenic agent, is upregulated during renal injury. The aim of this study was to investigate the potential relation between AngII and PTHrP system in the kidney. Different methods were used to find that both rat mesangial and mouse tubuloepithelial cells express PTHrP and the type 1 PTH/PTHrP receptor (PTH1R). In these cells, AngII increased PTHrP mRNA and protein production. In contrast, PTH1R mRNA was increased in mesangial cells and downregulated in tubular cells, but its protein levels were unmodified in both cells. AT(1) antagonist, but not AT(2), abolished AngII effects on PTHrP/PTH1R. The in vivo effect of AngII was further investigated by systemic infusion (a low dose of 50 ng/kg per min) into normal rats. In controls, PTHrP immunostaining was mainly detected in renal tubules. In AngII-infused rats, PTHrP staining increased in renal tubules and appeared in the glomerulus and the renal vessels. After AngII infusion, PTHR1 staining was markedly increased in all these renal structures at day 3 but remained elevated only in tubules at day 7. The AT(1) antagonist, but not the AT(2), significantly diminished AngII-induced PTHrP and PTHR1 overexpression in the renal tissue, associated with a decrease in tubular damage and fibrosis. The results indicate that AngII regulates renal PTHrP/PTH1R system via AT(1) receptors. These findings demonstrate that PTHrP upregulation occurs in association with the mechanisms of AngII-induced kidney injury.
Lorenzo
Oscar
O
Laboratory of Vascular and Renal Research, and Laboratory of Bone and Mineral Metabolism, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Ruiz-Ortega
Marta
M
Esbrit
Pedro
P
Rupérez
Mönica
M
Ortega
Arantxa
A
Santos
Soledad
S
Blanco
Julia
J
Ortega
Luis
L
Egido
Jesus
J
D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000032:analysis / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044168:Receptor, Parathyroid Hormone, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology; D018016:Receptors, Parathyroid Hormone / Q000032:analysis / Q000096:biosynthesis*; D015854:Up-Regulation
D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones; D044140:Receptor, Angiotensin, Type 1; D044168:Receptor, Parathyroid Hormone, Type 1; D011945:Receptors, Angiotensin; D018016:Receptors, Parathyroid Hormone; D000804:Angiotensin II