Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications

Abstract

Diabetic complication is comprised of a wide variety of pathophysiological factors involving proinflammatory cytokines, adipokines, and oxidative stress, among others. Each of these complications differs in their incidence and the stage of their occurrence. We examined cytokines and stress markers in 48 patients with type 2 diabetes mellitus and compared the difference of their contribution to pathogenesis between nephropathy and other diabetic complications. Hemoglobin A1c correlated with the level of low-density lipoprotein-cholesterol, and significantly elevated in the severe macroangiopathy group. Cystatin C increased in the severe microangiopathy groups but did not increase in the macroangiopathy group. The levels of interleukin 18 (IL-18), high-sensitive CRP (H-CRP), liver-type fatty acid binding protein, and 8-hydroxy-2-deoxyguanosine increased in the severe microangiopathy group. These data suggest the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy. In particular, IL-18 and H-CRP were significantly elevated only in the severe nephropathy group but did not significantly elevate in other complications. These data suggest another effect of IL-18 on glomerulus in addition to its proinflammatory effect. In conclusion, we propose that IL18 has a specific role that contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

Therapeutic Effect of Alprostadil in Diabetic Nephropathy: Possible Roles of Angiopoietin-2 and IL-18

“…Similar to Ang-2, both mRNA and protein levels of IL-18 were upregulated in diabetic mice compared with non-diabetic group, consistent with previous reports [10,11]. Moreover, four weeks of alprostadil treatment significantly reduced both mRNA and protein levels of IL-18 in diabetic mice (Fig.…”

“…For example, accumulating evidence suggests that IL-18 is a DN pathogenic cytokine. It has been reported that serum and urine IL-18 increase in patients with type 2 diabetes, which may be associated with the occurrence of DN [10,11]. However, how IL-18 functions in the pathogenesis of DN has not been fully elucidated.…”

Microinflammation as a Candidate for Diabetic Nephropathy

“…Besides, IL-18 levels increase in diabetic patients with the development of urinary albumin excretion [64]. So, elevated urinary excretion levels of IL-18 reported in patients with diabetic nephropathy seems to be closely related to the progression of diabetic nephropathy [63].…”

“…High-glucose concentrations and AGE may induce macrophage production of IL-12, which can stimulate CD4+ cell production of IFN-γ and augments natural killer cell activity [62,63]. Likewise, IFN-γ secretion by T-cells can initiate and further accelerates inflammation by the activation of macrophages and vascular cells and exacerbation of oxidative stress within renal tissues [32,16].…”

“…CX3CL1 (CX3C chemokine ligand 1; also known as fractalkine) exists in two forms as a membrane-anchored or as a shed 95 kDa glycoprotein. The soluble CX3CL1 has potent chemoattractant activity for T-cells and monocytes and induces adhesion between activated endothelial cells, which express its receptor CX3CR1 (CX3C chemokine receptor 1) [63].…”