Intercellular Adhesion Molecule-1–Deficient Mice Are Resistant Against Renal Injury After Induction of Diabetes

Okada, Shinichi; Shikata, Kenichi; Matsuda, Mitsuhiro; Ogawa, Daisuke; Usui, Hitomi; Kido, Yutaka; Nagase, Ryo; Wada, Jun; Shikata, Yasushi; Makino, Hírofumi

doi:10.2337/diabetes.52.10.2586

Cited by 267 publications

(248 citation statements)

References 42 publications

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“…ICAM-1 has been implicated in the firm adhesion step of inflammatory cell infiltration, and a deficiency of it causes suppression of diabetic nephropathy. 4,5 However, ICAM-1 expression was enhanced during the course of diabetic nephropathy in similar manner in Mdk þ / þ and Mdk À/À mice ( Figure 4D-F). Apparently enhanced expression of ICAM-1 was found in the peri-tubular vasculature at 2 months and afterwards in the two genotypes ( Figure 4D-F).…”

Section: Midkine In Tubulointerstitial Damagementioning

confidence: 89%

“…[26][27][28][29][30] Secondly, mice deficient in MCP-1 or ICAM-1 exhibit a marked reduction of nephropathy in the type I diabetes model with STZ. 4,6 MCP-1 or ICAM-1 deficiency also prevent nephropathy in type II diabetic db/db mice. 5,7 We found another key molecule for the inflammation in diabetic nephropathy in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6][7] However so far, only a few molecules have been identified as key players in this inflammation, that is, monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, nuclear factor-kB (NF-kB) and tumor necrosis factor-a. [3][4][5][6][7][8][9] We recently demonstrated that the growth factor midkine (MK) plays a critical role in the pathogenesis of diabetic nephropathy, using a mouse diabetes model induced by Streptozotocin (STZ). 10 STZ impairs b-cells in the pancreas, thereby inducing hyperglycemia, and thus has been used to induce type I diabetes mellitus in model systems.…”

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confidence: 99%

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Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

Kosugi

Yuzawa

Sato

et al. 2007

Laboratory Investigation

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The concept that inflammation plays a crucial role in the pathogenesis of diabetic nephropathy has been recently emerging, although the principal pathology of diabetic nephropathy comprises glomerular sclerosis and associated changes in nephrons. Here, we identified the growth factor midkine (MK) as a novel key molecule involved in inflammation associated with Streptozotocin-induced diabetic nephropathy. The tubulointerstitial damage, as assessed as morphological changes, osteopontin expression, collagen I deposition and macrophage infiltration, were strikingly less in MK-deficient (Mdk À/À ) mice than in Mdk þ / þ mice. Monocyte chemoattractant protein (MCP)-1 expression, but not that of intercellular adhesion molecule-1, was also lower in Mdk À/À mice. High glucose upregulated MK expression in primarycultured tubular epithelial cells, and induced MCP-1 to a larger extent in Mdk þ / þ cells than in Mdk À/À cells. Correspondingly, the combination of exogenous MK and high glucose enhanced MCP-1 expression in Mdk À/À cells. Furthermore, high glucose and oxidant stress enhanced MK expression in macrophages. Consistent with the findings in the mouse model, MK expression was detected in the glomeruli, tubular epithelium and interstitium of kidneys from patients with diabetic nephropathy. Our data indicate that MK plays a critical role in the tubulointerstitial inflammation associated with diabetic nephropathy through activation of the MCP-1 pathway.

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Section: Midkine In Tubulointerstitial Damagementioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

Kosugi

Yuzawa

Sato

et al. 2007

Laboratory Investigation

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“…[75][76][77] Prevention of diabetes-induced renal inflammation and associated renal damage in ICAM-1-or MCP-1-deficient animals provides further evidence of the participation of the inflammatory process in the pathogenesis of diabetic nephropathy. 78,79 Several lines of evidence have been shown to support the concept that a local inflammatory process is involved in the pathogenesis of DR. 80 Studies in humans using material from a vitrectomy or postmortem specimens from diabetic donors have demonstrated an association between inflammatory markers and the presence of DR. An increased expression of ICAM-1, which facilitates the trafficking of leukocytes into the retina, has been demonstrated in retinal blood vessels of post-mortem specimens from diabetic donors 81 and also in vitreous tissue of diabetic patients. 82 Concordantly, elevation in the intra-vitreous levels of two pro-inflammatory cytokines Interleukin-8 and MCP-1 was observed in diabetic patients with proliferative DR compared with non-diabetic subjects.…”

Section: Contribution Of Inflammation and Oxidative Stress To Dr And mentioning

confidence: 99%

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

2011

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Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of diabetic nephropathy and retinopathy. Large clinical trials have clearly demonstrated that tight control of glycemia and/or blood pressure significantly reduces the incidence and progression of diabetic retinopathy (DR) and nephropathy. However, the mechanism by which hypertension interacts with diabetes to induce and/or exacerbate nephropathy and retinopathy is very unclear. Substantial evidence implicates the involvement of chronic inflammation and oxidative stress in the pathogenesis of DR and nephropathy. In addition, hypertension causes oxidative stress and inflammation in the kidney and retina. In the present review, we summarized data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of diabetic nephropathy and retinopathy. It is suggested that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension.

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“…8,9 The important role of ICAM-1 on development of diabetic nephropathy was demonstrated using ICAM-1-deficient mice in which diabetes resulted in less glomerular injury with macrophage infiltration in kidney. 10 Similarly, MCP-1 expression is associated with macrophage infiltration in diabetic kidney. 3,11 MCP-1 and ICAM-1 may coordinate to stimulate leukocyte chemotaxis and adhesion, respectively.…”

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confidence: 99%

The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy

Sato

Kosugi

Zhang

et al. 2008

Laboratory Investigation

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A growing body of evidence implicates inflammation in the development of diabetic nephropathy. We recently reported that diabetic endothelial nitric oxide synthase knockout (eNOS KO) mice develop advanced glomerular lesions resembling human diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a major factor in diabetic nephropathy, and is known to be chemotactic for macrophages. Herein, we examined the association of VEGF with macrophage infiltration in experimental diabetic nephropathy. Glomerular macrophage infiltration was markedly increased in diabetic eNOS KO mice compared to diabetic C57BL/6 mice, and correlated with glomerular injury, such as mesangiolysis, glomerular microaneurysm and nodular lesions of glomerular sclerosis. An elevation of podocyte VEGF expression correlated with infiltration of Flt-1-positive macrophage in injured glomeruli in diabetic eNOS KO mice, suggesting that VEGF could contribute to macrophage migration. Neither renal nNOS nor iNOS expression was altered in both C57BL/6 and eNOS KO mice. To determine if lack of NO could affect VEGF activation of macrophages, we examined if exogenous NO can block macrophage migration induced by VEGF in in vitro studies. Exogenous NO blocked macrophage migration and hypertrophy in response to VEGF. NO mediated these effects in part by downregulating Flt-1 expression on the macrophage. In summary, NO negatively regulates VEGF-induced macrophage migration by inhibiting Flt-1 expression. The VEGF-endothelial NO uncoupling pathway might partially explain how VEGF causes glomerular disease in diabetes.

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Intercellular Adhesion Molecule-1–Deficient Mice Are Resistant Against Renal Injury After Induction of Diabetes

Cited by 267 publications

References 42 publications

Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy

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