Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. The primary initiating mechanism in DN is hyperglycemia-induced vascular dysfunction, but its progression is due to different pathological mechanisms, including oxidative stress, inflammatory cells infiltration, inflammation and fibrosis. Macrophages (Mφ) accumulation in kidneys correlates strongly with serum creatinine, interstitial myofibroblast accumulation and interstitial fibrosis scores. However, whether or not Mφ polarization is involved in the progression of DN has not been adequately defined. The prevalence of the different phenotypes during the course of DN, the existence of hybrid phenotypes and the plasticity of these cells depending of the environment have led to inconclusive results. In the same sense the role of the different macrophage phenotype in fibrosis associated or not to DN warrants additional investigation into Mφ polarization and its role in fibrosis. Due to the association between fibrosis and the progressive decline of renal function in DN, and the role of the different phenotypes of Mφ in fibrosis, in this review we examine the role of macrophage phenotype control in DN and highlight the potential factors contributing to phenotype change and injury or repair in DN.

Keywords: diabetic nephropathy; fibrosis; macrophages.

Figure 1

Macrophages in diabetic nephropathy. High glucose levels, tubular-reabsorbed protein, advanced glycation end products (AGEs), angiotensin-II (AT-II) and proinflammatory cytokines induce the production of MCP-1 by kidney tubular cells and podocytes. As a consequence, kidney monocyte recruitment is provoked. In the tissue, monocytes are converted in macrophages that acquire the M1, M2 or mixed phenotype depending on the inflammatory milieu and the molecules released by these different macrophage populations. M1 provokes injury and M2 are proresolution and regenerative macrophages that could induce fibrosis, while mixed macrophages could acquire different roles depending on the milieu. Macrophage image by Mikael Häggström, used with permission.