Renal expression of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor in a rat model of tubulointerstitial damage.
BACKGROUND
PTHrP, which appears to act as a growth/differentiation factor in a variety of tissues, is present in the kidney; however, its role is unclear.


METHODS
The expression of PTHrP and the PTH/PTHrP receptor were investigated by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry in the remnant kidney of uninephrectomized (UNX) rats after protein overloading [1 g/day of bovine serum albumin (BSA)].


RESULTS
Compared with UNX-control rats, proteinuria in BSA-overloaded animals was detected within the first 24 hours and increased during the entire study period (28 days). Kidney examination by light microscopy showed no significant renal lesions at day 1 of BSA treatment, whereas at days 8 and 28, tubular lesions, infiltration of mononuclear cells, and mesangial expansion were observed. PTHrP mRNA expression in the renal cortex was already increased at day 1 (fourfold) and plateaued between days 8 and 28 (12- and 15-fold, respectively) in BSA-overloaded animals compared with UNX-control rats. At day 8, immunohistochemical analysis with two different anti-PTHrP antibodies showed a dramatic increase of PTHrP staining in the damaged proximal and distal tubules from BSA-overloaded rats with respect to UNX-control rats. Moreover, intense PTHrP immunostaining was also observed in glomerular mesangial and endothelial cells in BSA-overloaded rats, but not in the UNX-control rats. A reciprocal decrease of PTH/PTHrP receptor mRNA and immunostaining, without significant changes in the cellular localization (proximal and distal tubule, and glomerular mesangial and epithelial cells) of the PTH/PTHrP receptor positivity was found to occur in the renal cortex of BSA-overloaded rats. At day 8, coinciding with the up-regulation of PTHrP, an increase in the angiotensin converting enzyme and preproendothelin-1 gene expression was observed in the renal cortex of BSA-overloaded rats compared with UNX-control rats.


CONCLUSIONS
These results indicate that PTHrP can be added to the group of genes that are up-regulated in proximal tubular cells in response to intense proteinuria. Our results, together with previous findings, suggest that the vasoactive hormones angiotensin II and endothelin-1 could participate in the PTHrP production in the renal cortex of BSA-overloaded rats. Further experiments are required to clarify the mechanisms of PTHrP up-regulation and its possible role in the response to renal damage in this animal model.
Largo
R
R
Renal Research Laboratory and Metabolic Research Unit, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Hospital Clínico, Universidad Complutense, Madrid, Spain.
Gómez-Garre
D
D
Santos
S
S
Peñaranda
C
C
Blanco
J
J
Esbrit
P
P
Egido
J
J
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D019332:Endothelin-1; D016232:Endothelins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009392:Nephrectomy; D044162:Parathyroid Hormone-Related Protein; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D011507:Proteinuria / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012710:Serum Albumin, Bovine / Q000008:administration & dosage
D017931:DNA Primers; D019332:Endothelin-1; D016232:Endothelins; D044162:Parathyroid Hormone-Related Protein; D011498:Protein Precursors; D011506:Proteins; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D012710:Serum Albumin, Bovine; D007703:Peptidyl-Dipeptidase A