Diabetic Nephropathy - The influence of glomerular endothelial cell activation on monocyte phenotype

One severe complication of living with diabetes for many years is diabetic nephropathy (DN) which affect about one third of all patients with type 1 or type 2 diabetes. When diabetic nephropathy leads to end stage renal disease, it is characterised by glomerular sclerosis and extensive fibrotic kidney lesions. Low grade inflammation with infiltration of monocytes and macrophages in the kidney is a key component in the fibrotic processes.

Monocytes originate in the bone marrow, circulate in the bloodstream and enter tissue where they differentiate into macrophages. The dominant monocyte phenotype expresses CD14 but not CD16 (CD14++CD16-) and nonclassical monocytes express CD16 and low levels of CD14 (CD14+CD16++)[1]. The macrophage phenotype is reflecting its activation status and is divided in an M0, M1 and M2 subgroup; however macrophage diversity is much more complex and extends beyond this paradigm.

In DN, the innate immune response is activated and monocytes infiltrate the glomerulus and tubulointerstitial compartment in the kidney of patients with type 2 diabetes and early nephropathy [2,3]. In mice with STZ-induced diabetes, DN is associated with increased renal abundance of both M1 and M2 macrophages [4] and in STZ-induced diabetic rats, DN is associated with increased renal infiltration of CD68 positive macrophages [5]. However, recent investigations have raised the possibility that it is the phenotype of the recruited macrophages rather than their presence alone that contributes to the fibrotic process.

The research objectives of the project are to:

1) Identify key signalling molecules arising from stimulated/activated glomerular endothelial cells (GEC) responsible for inducing phenotypic changes in monocytes and monocyte activation.

2) Characterize the key changes identified in activated monocytes upon endothelial mediated stimulation or by direct diabetes-relevant stimuli.

In the project, we aim at investigating the mechanistic cross-talk between human GECs and monocytes with focus on changes during initiation and development of type 2 diabetes and diabetic nephropathy.

Contact: Mette Dandanell Nielsen medani@sund.ku.dk

1. Martinez FO (2009) The transcriptome of human monocyte subsets begins to emerge. J Biol 8: 99.

2. Verzola D, Cappuccino L, D'Amato E, Villaggio B, Gianiorio F, et al. (2014) Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. Kidney Int 86: 1229-1243.

3. Nguyen D, Ping F, Mu W, Hill P, Atkins RC, et al. (2006) Macrophage accumulation in human progressive diabetic nephropathy. Nephrology (Carlton) 11: 226-231.

4. You H, Gao T, Cooper TK, Brian Reeves W, Awad AS (2013) Macrophages directly mediate diabetic renal injury. Am J Physiol Renal Physiol 305: F1719-1727.

5. Zhang XL, Guo YF, Song ZX, Zhou M (2014) Vitamin D prevents podocyte injury via regulation of macrophage M1/M2 phenotype in diabetic nephropathy rats. Endocrinology 155: 4939-4950.