Early glomerular macrophage recruitment in streptozotocin-induced diabeticrats

Diabetic glomerulosclerosis is defined by increased glomerular extracellula r matrix (ECM) that is mainly synthesized by mesangial cells that underwent an activation mediated by cytokines and growth factors from various cellul ar origins. In this study, we tested whether macrophages could infiltrate t he glomeruli and influence ECM synthesis in experimental diabetes, To test our hypothesis, we initially studied the dynamics of glomerular macrophage recruitment in streptozotocin-induced diabetic rats at days 1, 2, 4, 8, 15, and 30 by using quantitative reverse transcriptase-polymerase chain reacti on (RT-PCR) on isolated glomeruli and immunohistochemistry and morphometry, We then assessed the role of macrophages on the basis of the pharmacologic al modulation of their recruitment by insulin or ACE inhibitor treatments a nd by X-irradiation-induced macrophage depletion at days 8 and 30, Macropha ges were recruited within the glomeruli at the very early phase of hypergly cemia by using RT-PCR CD14 detection from day 2 and by using ED1 immunohist ochemistry from day 8, This glomerular macrophage infiltration was associat ed with an increase in alpha(1)-chain type IV collagen mRNA, In parallel, t he diabetic glomeruli became hypertrophic with an increase in the mesangial area. Macrophage recruitment was preceded by or associated with an increas ed glomerular expression of vascular cell adhesion molecule 1, intracellula r adhesion molecule 1, and monocyte chemoattractant protein 1, which contri butes to monocyte diapedesis, Glomerular interleukin-lp mRNA synthesis was also enhanced as early as day 1 and could be involved in the increase in EC M and adhesion molecule gene expressions. Insulin treatment and irradiation -induced macrophage depletion completely prevented the glomerular macrophag e recruitment and decreased alpha(1)-chain type IV collagen mRNA and mesang ial area in diabetic rats, whereas ACE inhibitor treatment had an incomplet e effect, It can be concluded that; in the streptozotocin model, hyperglyce mia is followed by an early macrophage recruitment that contributes to the molecular and structural events that could lead to glomerulosclerosis. Ther efore, besides direct stimulation of mesangial cells by hyperglycemia, macr ophages recruited in the glomeruli during the early phase of hyperglycemia could secondarily act on mesangial cells.