ACE Inhibitors Improve Diabetic Nephropathy Through Suppression of Renal MCP-1

Amann, Berthold; Tinzmann, Ralph; Angelkort, B

doi:10.2337/diacare.26.8.2421

Cited by 162 publications

(120 citation statements)

References 33 publications

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“…In the early stage of DN, several proinflammatory factors such as MCP-1, TNF-␣, ICAM-1, and IL-18, have been found to be upregulated (21)(22)(23). MCP-1 is a major chemokine inducing monocyte migration and differentiation to macrophages, which augment ECM production and interstitial fibrosis in diabetic kidney (17,43,44). In this study, we demonstrate that angiostatin significantly blocks high-glucose-and TGF-␤-induced MCP-1 secretion in mesangial cells, suggesting that angiostatin inhibits inflammation in DN.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic Potential of Angiostatin in Diabetic Nephropathy

Zhang¹,

Wang²,

Lu³

et al. 2006

Journal of the American Society of Nephrology

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Angiostatin is a proteolytic fragment of plasminogen and a potent angiogenic inhibitor. Previous studies have shown that angiostatin inhibits retinal neovascularization and reduces retinal vascular permeability in diabetic retinopathy. Here, it is reported for the first time that angiostatin is also implicated in diabetic nephropathy (DN). Angiostatin levels are dramatically decreased in the kidney of streptozotocin-induced diabetic rats. Consistently, diabetic kidneys also showed decreased expression and proteolytic activities of matrix metalloproteinase-2, an enzyme that releases angiostatin from plasminogen. Adenovirus-mediated delivery of angiostatin significantly alleviated albuminuria and attenuated the glomerular hypertrophy in diabetic rats. Moreover, angiostatin treatment downregulated the expression of vascular endothelial growth factor and TGF-␤1, two major pathogenic factors of DN, in diabetic kidneys. In cultured human mesangial cells, angiostatin blocked the overexpression of vascular endothelial growth factor and TGF-␤1 that were induced by high glucose while increasing the levels of pigment epithelium-derived factor, an endogenous inhibitor of DN. Moreover, angiostatin effectively inhibited the high-glucose-and TGF-␤1-induced overproduction of proinflammatory factors and extracellular matrix proteins via blockade of the Smad signaling pathway. These findings suggest that the decrease of angiostatin levels in diabetic kidney may contribute to the pathologic changes such as inflammation and fibrosis in DN. Therefore, angiostatin has therapeutic potential in DN as a result of its anti-inflammatory and antifibrosis activities.

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Section: Discussionmentioning

confidence: 99%

“…MCP-1 is one of the most important proinflammatory chemokines implicated in the pathogenesis of DN (17,43,44). High glucose is known to upregulate MCP-1 expression via the NF-B activation in cultured renal mesangial cells (45).…”

Section: Angiostatin Decreases High-glucose-and Tgf-␤1-induced Mcp-1 mentioning

confidence: 99%

Therapeutic Potential of Angiostatin in Diabetic Nephropathy

Zhang¹,

Wang²,

Lu³

et al. 2006

Journal of the American Society of Nephrology

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“…As monocyte chemoattractant protein-1 induces monocyte immigration and differentiation to macrophages, which augment extracellular matrix production and tubulointerstitial fibrosis, pharmacological reduction of Ang II may also exert its beneficial effects in diabetic nephropathy by downregulation of renal monocyte chemoattractant protein-1. 64 …”

Section: Diabetic Nephropathymentioning

confidence: 99%

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

2009

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Since their inception, angiotensin-converting enzyme (ACE) inhibitors have been used as first-line therapy for the treatment of cardiovascular and renal diseases. They restore the balance between the vasoconstrictive salt-retentive and hypertrophy-causing peptide angiotensin II (Ang II) and bradykinin, a vasodilatory and natriuretic peptide. As ACE is a promiscuous enzyme, ACE inhibitors alter the metabolism of a number of other vasoactive substances. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have been proven effective in the treatment of hypertension, and reduce mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction. They inhibit ischemic events and stabilize plaques. Furthermore, they delay the progression of diabetic nephropathy and neuropathy and act as antioxidants. Ongoing studies have elucidated protective roles for them in both memory-related disorders and cancer. INTRODUCTIONIn recent years, stressful and fiercely competitive lifestyles and food habits have compounded the problems of hypertension. Long-standing and stressful, progressively rising hypertension can lead to many disorders, including myocardial infarction (MI), cerebrovascular events, congestive heart failure, peripheral arterial insufficiency, premature mortality 1 and renal dysfunction leading to glomerulosclerosis and kidney artery aneurysm. 2 A number of therapies are available, but angiotensin-converting enzyme (ACE) inhibitors have been the preferred first-line therapy for hypertension, congestive heart failure, left ventricular (LV) systolic dysfunction and MI. 3,4 ACE inhibitors (ACEis) have been in use for the past two decades, and the interest in them is still growing. Recently, the discovery of domain-selective ACEis and new members of the renin-angiotensin system (RAS) (that is, angiotensin-converting enzyme 2) have again fueled the interest of researchers. Some new studies have expanded the already impressive clinical profile of ACEis. This review traces some already known and new facets of ACE inhibition and introduces new advances in the designing of a new generation of ACEis.

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“…One of the pleiotropic protective effects of RAAS blockade on the kidney in patients with overt diabetic nephropathy is anti-inflammatory activity [15]. The ability of clinicians to suppress renal inflammation may have particularly important implications for patients with uncomplicated type 1 diabetes mellitus, in whom urinary inflammatory markers may be the only sign of kidney disease prior to the onset of microalbuminuria or declining kidney function [11].…”

Section: Introductionmentioning

confidence: 99%

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

et al. 2013

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Aims/hypothesis Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy. Methods Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/ chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n=27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days. Results Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188±0.007 to 0.206±0.007, p=0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p<0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p=0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p<0.005). Conclusions/interpretation The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

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ACE Inhibitors Improve Diabetic Nephropathy Through Suppression of Renal MCP-1

Cited by 162 publications

References 33 publications

Therapeutic Potential of Angiostatin in Diabetic Nephropathy

Therapeutic Potential of Angiostatin in Diabetic Nephropathy

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

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