Abstract
BackgroundIn experimental models of diabetes mellitus, aggravation of renal injury by concomitant hypertension has been described. Inflammatory mechanisms contribute to renal damage in both diseases. We investigated whether hypertension and diabetes mellitus act synergistically to induce macrophage infiltration and matrix expansion in the kidney.MethodsInsulin-dependent diabetes mellitus was induced by streptozotocin injections to hypertensive mRen2-transgenic rats (TGR) and normotensive Sprague-Dawley control rats. Quantitative immunohistochemical examination of kidney tissue sections was used to measure macrophage infiltration and matrix expansion. The expression of MCP-1, Osteopontin, RANTES, ICAM-1 and VCAM-1 was evaluated by real-time RT-PCR. The localization of MCP-1 was studied by immunohistochemistry.ResultsMacrophage infiltration was present in the kidney of normotensive diabetic rats. Hypertensive rats exhibited a more marked infiltration of macrophages, regardless of whether diabetes was present or not. Gene expression of ICAM-1, VCAM-1 and RANTES was unaltered whereas Osteopontin and MCP-1 were induced by hypertension. Immunoreactive MCP-1 was slightly increased in diabetic rat kidney podocytes, and more markedly increased in hypertensive animals. Glomerular matrix accumulation was induced by diabetes and hypertension to a similar degree, and was highest in hypertensive, diabetic animals.ConclusionDiabetes mellitus caused a mild, and angiotensin-dependent hypertension a more marked infiltration of macrophages in the kidney. Combination of both diseases led to additive effects on matrix expansion but not on inflammation. Hypertension appears to be a much stronger stimulus for inflammation of the kidney than STZ diabetes, at least in mRen2-transgenic rats.
Highlights
In experimental models of diabetes mellitus, aggravation of renal injury by concomitant hypertension has been described
The finding that monocyte chemoattractant protein-1 (MCP-1) is likewise induced in renal mesangial cells by high glucose concentrations [6] is in keeping with the hypothesis that chronic inflammatory mechanisms may contribute to the pathogenesis of diabetic nephropathy [7]
In untreated transgenic rats (TGR), blood glucose did not differ from untreated SD rats
Summary
In experimental models of diabetes mellitus, aggravation of renal injury by concomitant hypertension has been described. We investigated whether hypertension and diabetes mellitus act synergistically to induce macrophage infiltration and matrix expansion in the kidney. In most patients with diabetic nephropathy, hypertension is present and contributes significantly to the progression of renal failure in diabetes [1]. Angiotensin II-induced hypertension leads to macrophage infiltration in the kidney, and chemokines have been proposed as mediators of macrophage infiltration [3,4]. The chemokine monocyte chemoattractant protein-1 (MCP-1) can be induced in vascular smooth muscle cells by angiotensin II [5]. The finding that MCP-1 is likewise induced in renal mesangial cells by high glucose concentrations [6] is in keeping with the hypothesis that chronic inflammatory mechanisms may contribute to the pathogenesis of diabetic nephropathy [7]. Induction of chemokines in the diabetic kidney seems to enhance macrophage infiltration [8,9,10,11,12]
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