Increased Osteopontin Expression following Renal Ablation Is Attenuated by Angiotensin Type 1 Receptor Antagonism

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Abstract

Osteopontin is an extracellular matrix protein that is upregulated in renal injury. The aim of this study was to explore the renal expression of osteopontin in a model of progressive renal injury following subtotal nephrectomy (STNx) in rats and the effects of angiotensin type1 (AT1) receptor antagonist irbesartan on osteopontin expression. STNx or a sham operation was performed in 8-week-old Sprague-Dawley rats. STNx rats were given either irbesartan (15 mg/g) or no treatment for 12 weeks. Upregulation of osteopontin mRNA expression was observed in injured renal tubules as assessed by in situ hybridization (42 ± 8 dpm/mm2 v.s. control 7.7 ± 0.6 dpm/mm2, p < 0.01). Increased osteopontin expression was closely related to infiltration of monocytes/macrophages and increased cellular proliferation. Double immunohistochemical staining demonstrated co-existence of proliferating cell nuclear antigen and osteopontin positive staining in individual cells in kidney sections from STNx rats. The increase in osteopontin expression was inhibited by the AT1 receptor antagonist irbesartan (6.9 ± 1.2 dpm/mm2), associated with attenuation of impaired renal function and pathology as well as decreased monocyte/macrophage infiltration and cellular proliferation. These findings suggest that osteopontin is upregulated in STNx rats and is reduced by AT1 receptor antagonism.

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De novo glomerular osteopontin expression in rat crescentic glomerulonephritis.

Emily Atkins, N Yang, Haw-Chang H Lan … (1997)

Osteopontin (OPN) is a secreted acidic glycoprotein that has potent monocyte chemoattractant and adhesive properties. Up-regulation of tubular OPN expression is thought to promote interstitial macrophage infiltration in experimental nephritis; however, the role of OPN in glomerular lesions, particularly crescent formation, is unknown. The present study used Northern blotting, in situ hybridization and immunohistochemistry to examine OPN expression in a rat model of accelerated anti-GBM glomerulonephritis. Osteopontin mRNA and protein is expressed by some parietal epithelial cells, thick ascending limbs of Henle and medullary tubules and collecting ducts in normal rat kidney. De novo OPN mRNA and protein expression was evident in glomerular visceral and parietal epithelial cells in anti-GBM glomerulonephritis. Glomerular OPN expression preceded and correlated with macrophage infiltration in the development of hypercellularity, focal and segmental lesions and, notably, crescent formation. There was marked up-regulation of OPN expression by tubular epithelial cells that also preceded and correlated with interstitial macrophage (r = 0.93, P < 0.001) and T-cell infiltration (r = 0.85, P < 0.001). Both glomerular and tubular OPN expression correlated significantly with proteinuria (P < 0.001) and a reduction in creatinine clearance (P < 0.01). In addition, double immunohistochemistry showed co-expression of osteopontin and one of its ligands, CD44, in intrinsic renal cells. CD44 and OPN expression by parietal epithelial cells was evident in crescent formation, while virtually all OPN-positive tubules expressed CD44. Infiltrating macrophages and T-cells were CD44-positive, but only a small proportion of T-cells and few macrophages showed OPN expression. Interestingly, strong OPN mRNA and protein expression was seen in macrophage multinucleated giant cells. In summary, this study suggests that OPN promotes macrophage and T-cell infiltration in the development of renal lesions in rat anti-GBM glomerulonephritis, including glomerular crescent and multinucleated giant cell formation.

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Link between Angiotensin II and TGF-β in the Kidney

Gunter Wolf (1998)

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Regulation of proximal tubular osteopontin in experimental hydronephrosis in the rat.

Nágila Ricardo, R Kreisberg-Zakarin, Don J. Diamond … (1998)

Osteopontin is a tubular-derived glycoprotein with macrophage chemoattractant properties. Our previous observations demonstrate that osteopontin is involved in the accumulation of macrophages within the renal cortex of rats following unilateral ureteral obstruction (UUO). The present study performed Northern and Western blot analyses of isolated proximal tubular cells exposed to exogenous angiotensin II, and cultured rat proximal tubular cells subjected to one hour of cyclic mechanical stretch, which provided insight into mechanisms involving the proximal tubular renin-angiotensin system in the increased expression of cortical osteopontin following hydronephrosis. In situ hybridization, using a 35S-labeled antisense riboprobe, showed osteopontin mRNA transcription localized to the cortical tubules of the obstructed kidney. Freshly isolated proximal tubules incubated with angiotensin II (10-5 M) for one hour had increased osteopontin mRNA and protein expression by Northern and Western blot analyses, respectively. Pre-treatment of proximal tubules with losartan (10-5 M) for one hour prior to the addition of exogenous angiotensin II (10-5 M) decreased osteopontin mRNA and protein expression. Rat proximal tubule cells subjected to cyclic mechanical stretch for one hour exhibited a 2.1-fold increment in osteopontin mRNA levels, which was normalized following pre-treatment with losartan. This study provides evidence that angiotensin II, produced by the proximal tubule in the obstructed kidney as a result of mechanical injury, possibly mechanical stretch, may stimulate angiotensin II type I receptor activation, leading to up-regulated osteopontin expression and secretion by the proximal tubule, thereby facilitating macrophage recruitment into the renal interstitium.

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Journal

Journal ID (publisher-id): EXN

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2002

Publication date (Print): 2002

Publication date (Electronic): 09 January 2002

Volume: 10

Issue: 1

Pages: 19-25

Affiliations

Department of Medicine, University of Melbourne, Austin & Repatriation Medical Center, Heidelberg West, Vic.,Australia

Article

Publisher ID: 49894 Other ID: Exp Nephrol 2002;10:19–25

DOI: 10.1159/000049894

SO-VID: 317f4c4c-8fa1-4c6e-982d-6b7cbb89e3f2

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Increased Osteopontin Expression following Renal Ablation Is Attenuated by Angiotensin Type 1 Receptor Antagonism

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Abstract

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Karger: Nephrology

Most cited references 3

De novo glomerular osteopontin expression in rat crescentic glomerulonephritis.

Link between Angiotensin II and TGF-β in the Kidney

Regulation of proximal tubular osteopontin in experimental hydronephrosis in the rat.

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