Osteopontin expression in progressive renal injury in remnant kidney: role of angiotensin II.
BACKGROUND
Osteopontin (OPN) is a macrophage chemotactic and adhesion molecule and has been shown to play a role in glomerular and tubulointerstitial injury in several kidney disease models.


METHODS
The present study examined whether OPN expression is involved in the progression of renal disease following subtotal (5/6) nephrectomy (STNx) in rats and whether angiotensin II (Ang II) mediates the up-regulation of renal OPN expression and macrophage accumulation in this model by administering valsartan, an Ang II type I (AT1) receptor antagonist, or ramipril, an angiotensin-converting enzyme (ACE) inhibitor.


RESULTS
In normal and sham-operated rat kidneys, OPN was expressed in a few tubules (<5%) and was absent in glomeruli. Following STNx (weeks 2 to 16), there was substantial up-regulation of OPN mRNA and protein expression in glomeruli [2 to 12 cells/glomerular cross section (gcs)] and tubular epithelial cells (20 to 75% OPN+). The up-regulation of OPN expression was associated with macrophage accumulation within the kidney, severe proteinuria, loss of renal function, and severe histologic damage, including tubulitis and tubulointerstitial fibrosis (all P < 0.001). Treatment with either valsartan or ramipril completely abrogated the up-regulation of OPN mRNA and protein expression in glomeruli and tubules. The reduction in OPN expression was associated with a significant inhibition of macrophage accumulation and progressive renal injury (P < 0.001).


CONCLUSIONS
An up-regulation of OPN expression may play a role in progressive renal injury following STNx. Inhibition of OPN expression may be one of the mechanisms by which Ang II blockade attenuated renal injury after renal ablation.
Yu
X Q
XQ
Department of Nephrology, The First Hospital, Sun Yat-Sen University of Medical Sciences, Guangzhou, People's Republic of China.
Wu
L L
LL
Huang
X R
XR
Yang
N
N
Gilbert
R E
RE
Cooper
M E
ME
Johnson
R J
RJ
Lai
K N
KN
Lan
H Y
HY
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015152:Blotting, Northern; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D017403:In Situ Hybridization; D007668:Kidney / Q000502:physiology* / Q000601:surgery; D008264:Macrophages / Q000473:pathology; D008297:Male; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D053495:Osteopontin; D012333:RNA, Messenger / Q000032:analysis; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000235:genetics* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D013777:Tetrazoles; D053495:Osteopontin; D000804:Angiotensin II; D000068756:Valsartan; D014633:Valine; D017257:Ramipril