Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats

Abstract

Renin-angiotensin blockade lowers MCP-1 expression in dia-to precede the earliest manifestations of diabetic betic rats.nephropathy [1][2][3]. In rats made diabetic with streptozo-Background. Glomerular macrophage accumulation in diatocin (STZ) and maintained at moderate levels of hyperbetes implicates monocyte recruitment mechanisms in the glycemia by daily insulin injections, glomerular hyperpathogenesis of diabetic nephropathy. To test the hypothesis filtration, caused by elevations of glomerular perfusion that overexpression of monocyte chemoattractant protein-1 (MCP-1), a monocyte chemoattractant, is attenuated by reninand intracapillary hydraulic pressure (glomerular capilangiotensin system (RAS) inhibition, we assessed expression lary hypertension), likewise presages glomerular injury of genes regulating monocyte transmigration in the glomeruli [4]. Both glomerular capillary hypertension and the subof diabetic rats. sequent development of glomerular injury are dependent Methods. Competitive reverse transcription-polymerase chain on an intact renin-angiotensin system (RAS), as revealed reaction (RT-PCR) was used to semiquantitate mRNA expression in glomeruli harvested by sieving at serial intervals after by earlier studies from this laboratory showing that treatthe induction of diabetes by streptozotocin in Munich-Wistar ment with angiotensin-converting enzyme inhibitors rats. Although subject to limitations, competitive RT-PCR pro-(ACEIs) [5], alleviated glomerular capillary hypertenvides an objective measure suited to the minute quantities of sion and prevented the development of diabetic ne-RNA extractable from glomerular isolates. Results. Time-dependent elevation of MCP-1 expression phropathy in STZ rats, independent of glycemic control. was dramatically suppressed by treatment with the angiotensin-These studies established the experimental basis for the converting enzyme inhibitor enalapril or the AT1 receptor antagfirst successful large-scale clinical trial of ACEI in type onist candesartan, and was closely associated with effects on I diabetic patients [6]. proteinuria and glomerular macrophage number. By contrast, Glomerular injury occurring in the context of angiono sustained suppression of the cell adhesion molecules intercellular adhesion molecule-1 or vascular cell adhesion moletensin-dependent processes, including augmented glocule-1 or the classic MCP-1 stimulators tumor necrosis factor-␣ merular hemodynamics, may involve mononuclear cells or interleukin-1␤ followed RAS inhibition, and suppression of and an array of cytokines and other proinflammatory transforming growth factor-␤1 expression was transient. molecules. Evidence is accumulating that supports theConclusion. These data suggest that glomerular macrophage recruitment in experimental diabetes is largely determined by hypothesis that macrophages and macrophage products angiotensin-stimulated MCP-1 expression. We conclude that play a significant role not only in inflammatory glomeruthe RAS is an important regulator of local MCP-1 expre...

Evidence for renoprotection by blockade of the renin–angiotensin–aldosterone system in hypertension and diabetes

“…27 Monocyte chemoattractant protein-1 (MCP-1), a key inflammatory mediator in the pathogenesis of nephropathy, has been implicated in matrix accumulation and diabetic nephropathy; MCP-1 is also increased in angiotensin-induced hypertension. 28 Elevated intraluminal pressure can also lead to downregulation of tissue plasminogen activator, a promoter of fibrinolysis/thrombolysis, which is impaired in patients with hypertension. 29 Angiotensin II also increases production of plasminogen activator inhibitor-1, which is both a major inhibitor of fibrinolysis and is antiproteolytic, thus promoting matrix accumulation.…”

“…7 The renoprotective effects of ACE inhibitors and ARBs, including reduction of albuminuria and improvements in glomerular histology, 4,51 appear to be at least partly independent of their BP-lowering effects. 40,52 Studies in animal models of diabetes or hypertension suggest that the therapeutic benefits of ARBs and ACE inhibitors might be mediated through a number of mechanisms, including suppression of MCP-1, 28 inhibition of collagen synthesis and stimulation of metalloproteinase activity, 27 prevention of loss of glomerular nephrin, 53 and prevention of overexpression of TGF-b1 and type IV collagen. 54 Evidence also suggests that improved glomerular permselectivity may contribute to renoprotection.…”

Activation of the Heart by Donor Brain Death Accelerates Acute Rejection After Transplantation

“…13 Reverse transcription was carried out in a total volume of 20 L containing 4 g of RNA; 0.5 mmol/L each of dATP, dCTP, dGTP, and dTTP; 0.6 g oligo-d(T) [12][13][14][15][16][17][18] cDNA was used as substrate for competitive polymerase chain reaction (PCR) with DNA mimics constructed with a PCR Mimic Construction Kit (Clontech Laboratories Inc) for rat MCP-1, TNF-␣, IL-1␤, and GAPDH. Primer sets were designed on the basis of published cDNA sequences and have previously been used in published studies.…”

“…This method is as accurate as scintillation counting of radiolabeled PCR products. 16 The cell products examined in these studies (TNF-␣, IL-1␤, MCP-1) were chosen as representative of early inflammatory and immunological host events, as shown in previous models of I/R injury and acute allograft rejection. 17,18 …”

Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells

“…In vitro, mesangial cell exposure to stretch and high glucose induces MCP-1 production resulting in monocyte chemotaxis [4]. In vivo, MCP-1 is overproduced in the glomeruli in experimental diabetes, an event paralleled by monocyte infiltration [5,6]. Infiltrating monocytes release inflammatory cytokines that enhance fibronectin production in mesangial cells [7], a possible mechanism whereby MCP-1 may contribute to fibronectin deposition in the diabetic glomeruli.…”