Long-term treatment with ramipril attenuates renal osteopontin expression in diabetic rats

Li, Can; Yang, Chul Woo; Park, Cheol Whee; Ahn, Hyo Jun; Kim, Wan Young; Yoon, Kun Ho; Suh, Sun Hee; Lim, Sun Woo; Ho, Jung; Kim, Yong Soo; Kim, Jin; Chang, Yoon Sik; Bang, Byung Kee

doi:10.1046/j.1523-1755.2003.00751.x

Cited by 50 publications

(48 citation statements)

References 49 publications

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“…74 Several animal studies have shown that Ang-II upregulates OPN expression, whereas the blockade of Ang-II by using an ACE inhibitor, such as ramipril, suppresses inflammatory cytokine OPN expression. 75 Our data demonstrate that ramipril was associated with a modest 12% reduction in plasma OPN levels.…”

Section: Inflammation and Adhesionmentioning

confidence: 55%

Potential Vascular Mechanisms of Ramipril Induced Increases in Walking Ability in Patients With Intermittent Claudication

Ahimastos

Latouche

Natoli

et al. 2014

Circulation Research

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Rationale: We recently reported that ramipril more than doubled maximum walking times in patients with peripheral artery disease with intermittent claudication. Objective: Our aim was to conduct exploratory analyses of the effects of ramipril therapy on circulating biomarkers of angiogenesis/arteriogenesis, thrombosis, inflammation, and leukocyte adhesion in patients with intermittent claudication. Methods and Results: One hundred sixty-five patients with intermittent claudication (mean, 65.3 [SD, 6.7] years) were administered ramipril 10 mg per day (n=82) or matching placebo (n=83) for 24 weeks in a randomized, double-blind study. Plasma biomarkers of angiogenesis/arteriogenesis (vascular endothelial growth factor-A, fibroblast growth factor-2), thrombosis (D-dimer, von Willebrand factor, thrombin-antithrombin III), inflammation (high-sensitivity C-reactive protein, osteopontin), and leukocyte adhesion (soluble vascular cell adhesion molecule-1, soluble intracellular adhesion molecule-1) were measured at baseline and 24 weeks. Relative to placebo, ramipril was associated with increases in vascular endothelial growth factor-A by 38% (95% confidence interval [CI], 34%–42%) and fibroblast growth factor-2 by 64% (95% CI, 44–85%; P <0.001 for both), and reductions in D-dimer by 24% (95% CI, −30% to −18%), von Willebrand factor by 22% (95% CI, −35% to −9%), thrombin-antithrombin III by 16% (95% CI, −19% to −13%), high-sensitivity C-reactive protein by 13% (95% CI, −14% to −9%), osteopontin by 12% (95% CI, −14% to −10%), soluble vascular cell adhesion molecule-1 by 14% (95% CI, −18% to −10%), and soluble intracellular adhesion molecule-1 by 15% (95% CI, −17% to −13%; all P <0.001). With the exception of von Willebrand factor, all the above changes correlated significantly with the change in maximum walking time ( P =0.02−0.001) in the group treated with ramipril. Conclusions: Ramipril is associated with an increase in the biomarkers of angiogenesis/arteriogenesis and reduction in the markers of thrombosis, inflammation, and leukocyte adhesion. This study informs strategies to improve mobility in patients with intermittent claudication. Clinical Trial Registration Information: URL: http://clinicaltrials.gov . Unique identifier: NCT00681226.

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Section: Inflammation and Adhesionmentioning

confidence: 55%

Potential Vascular Mechanisms of Ramipril Induced Increases in Walking Ability in Patients With Intermittent Claudication

Ahimastos

Latouche

Natoli

et al. 2014

Circulation Research

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“…For many years, it has been well known that OPN is upregulated in the interstitium, especially the proximal tubules, in the diabetic kidney. [12][13][14] Moreover, OPN deficiency prevents the development of diabetic nephropathy in murine models. 19,20 We recently reported that a peroxisome proliferator-activated receptor d agonist, GW0742, attenuates diabetic nephropathy by suppressing inflammatory mediators, including OPN and MCP-1.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 Because OPN is a macrophage chemotactic protein, OPN expression and macrophage accumulation may play a role in the tubulointerstitial injury in diabetic nephropathy in rats 13,14 and mice. 15,16 Moreover, we and others have shown by DNA microarray studies that OPN gene expression is upregulated in the renal cortex and correlated with the degree of albuminuria in diabetic nephropathy, [16][17][18] suggesting that regulation of OPN expression could be a potential target for therapeutic intervention in diabetic nephropathy.…”

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confidence: 99%

Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy

Tachibana¹,

Ogawa

Matsushita³

et al. 2012

Journal of the American Society of Nephrology

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Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.

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“…The severity of glomerular proliferation, interstitial fibrosis, and tubular proteinaceous cast scores were evaluated using light microscopy according to previously described methods (4,25,(33)(34)(35)(36)(37). Briefly, glomerular proliferative lesions were scored into five grades as follows: 0, no proliferation; 1, minor (segmental lesion Ͻ25%); 2, mild (segmental lesion Ͼ25% but Ͻ50%); 3, moderate (diffuse proliferation without severe sclerotic change); and 4, severe (diffuse proliferation with nearly complete sclerosis) (4,33,34,36).…”

Section: Histologic Examinationmentioning

confidence: 99%

“…A minimum of 40 glomeruli were examined in each PAS-stained specimen. The severity of tubulointerstitial fibrosis was assessed by counting the percentage of injured areas per field and then scored as follows: 0, normal interstitium; 0.5, Ͻ5% of areas injured; 1, 5 to 15%; 1.5, 16 to 25%; 2, 26 to 35%; 2.5, 36 to 45%; and 3, Ͼ45% (35,36). A minimum of 20 fields were evaluated for each Masson's trichromestained specimen.…”

Section: Histologic Examinationmentioning

confidence: 99%

Involvements of Rho-Kinase and TGF-β Pathways in Aldosterone-Induced Renal Injury

Sun

Kohno

Guo

et al. 2006

Journal of the American Society of Nephrology

110

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Recent studies have suggested a role for aldosterone in the pathogenesis of renal injury. This study investigated the potential contributions of Rho-kinase and TGF-␤ pathways to aldosterone-induced renal injury. Rats were uninephrectomized and then treated for 5 wk with 1% NaCl in a drinking solution and one of the following: Vehicle (2% ethanol, subcutaneously; n ‫؍‬ 9); aldosterone (0.75 g/h, subcutaneously; n ‫؍‬ 9); or aldosterone ؉ fasudil, a specific Rho-kinase inhibitor (10 mg/kg per d, subcutaneously; n ‫؍‬ 8). Phosphorylation of myosin phosphate target subunit-1 (MYPT1) and Smad2/3 in renal cortical tissue was measured by Western blotting with anti-phospho MYPT1 and Smad2/3 antibodies, respectively. Rats that received aldosterone infusion exhibited hypertension and severe renal injury characterized by proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis with increases in ␣-smooth muscle actin staining and numbers of monocytes/macrophages in the interstitium. Renal cortical mRNA levels of types I and III collagen, TGF-␤, connective tissue growth factor, and monocyte chemoattractant protein-1 as well as Smad2/3 phosphorylation were significantly increased in rats that received aldosterone infusion. All of these changes were associated with an increase in renal tissue MYPT1 phosphorylation. Treatment with fasudil did not alter BP but significantly ameliorated proteinuria and renal injury in rats that received aldosterone infusion. Severe glomerular injury and interstitial fibrosis were observed in rats that were treated long term with aldosterone/ salt (3,4). Moreover, exogenous infusion of aldosterone reversed the renoprotective effects of angiotensin II blockade in remnant kidney hypertensive rats (5). In stroke-prone spontaneously hypertensive rats (6); Dahl salt-sensitive hypertensive rats (7); and rats that were treated with angiotensin II and a nitric oxide synthase inhibitor (8), cyclosporine A (9), or radiation (10), treatment with mineralocorticoid receptor (MR) antagonists had no effect on systemic BP (SBP) but significantly ameliorated renal injury. In patients with chronic renal failure (11) and early diabetic nephropathy (12), the addition of MR antagonists to angiotensin-converting enzyme (ACE) inhibitors had no hemodynamic effects but markedly reduced proteinuria. Further studies also showed that monotherapy with MR antagonists was more effective than ACE inhibitors in reducing proteinuria in hypertensive patients (13,14). We recently found that aldosterone stimulates reactive oxygen species production (15) and induces cell proliferation (16) or deformation (16) in cultured glomerular mesangial cells. In addition, aldosterone stimulated collagen synthesis in cultured renal fibroblasts (17). Collectively, these data suggest that aldosterone has deleterious effects on the kidney that cannot be explained simply by BP changes. However, the precise mechanisms that are responsible for aldosterone-induced renal injury remain undetermined.Rho-kinase, an effector of the small G protein ...

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Long-term treatment with ramipril attenuates renal osteopontin expression in diabetic rats

Abstract: Up-regulation of OPN expression may play a role in tubulointerstitial injury associated with diabetic nephropathy, and blockade of the RAS by ramipril may confer renoprotection by decreasing OPN expression in non-insulin-dependent diabetic nephropathy.

Cited by 50 publications

References 49 publications

Potential Vascular Mechanisms of Ramipril Induced Increases in Walking Ability in Patients With Intermittent Claudication

Potential Vascular Mechanisms of Ramipril Induced Increases in Walking Ability in Patients With Intermittent Claudication

Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy

Involvements of Rho-Kinase and TGF-β Pathways in Aldosterone-Induced Renal Injury

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