Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and a main contributing factor for cardiovascular morbidity and mortality in patients with diabetes mellitus. Strategies employed to delay the progression of this pathology focus on the control of traditional risk factors, such as hyperglycemia, and elevated blood pressure. Although the intimate mechanisms involved in the onset and progression of DKD remain incompletely understood, inflammation is currently recognized as one of the main underlying processes. Untangling the mechanisms involved in the appearing of a harmful inflammatory response in the diabetic patient is crucial for the development of new therapeutic strategies. In this review, we focus on the inflammation-related pathogenic mechanisms involved in DKD and in the therapeutic utility of new anti-inflammatory strategies.

Cardiovascular disease is the leading cause of death worldwide. New therapeutic strategies are aimed to modulate the athero-inflammatory process that partially orchestrates underlying vascular damage. Peripheral blood circulating cells include different immune cells with a central role in the development of the atherogenic inflammatory response. The anti-aging protein α-Klotho has been related to protective effects against CVD. KL is expressed in monocytes, macrophages, and lymphocytes where it exerts anti-inflammatory effects. In this work, we analyse the relationships of the levels of inflammatory markers with the expression of the KL gene in PBCCs and with the serum levels of soluble KL in atherosclerotic vascular disease. For this, we conducted a cross-sectional single-center case–control study including a study group of 76 CVD patients and a control group of 16 cadaveric organ donors without medical antecedent or study indicating CVD. Vascular artery fragments and whole blood and serum samples were obtained during elective or organ retrieval surgery. Serum levels of sKL, TNFα and IL10, and gene expression levels of KL, TNF, IL10, NFKB1, DNMT1, and DNMT3A in PBCCs were measured. In these cells, we also determined KL promoter methylation percentage. Histological and immunohistochemical analyses were employed to visualize atherosclerotic lesions and to measure IL10 and TNFα levels in vascular fragments. Patients with CVD presented higher values of proinflammatory markers both at systemic and in the vasculature and in the PBCCs, compared to the control group. In PBCCs, CVD patients also presented lower gene expression levels of KL gene (56.4% difference, P < 0.001), higher gene expression levels of DNMT1 and DNMT3A (P < 0.0001, for both) and a higher methylation status of in the promoter region of KL (34.1 ± 4.1% vs. 14.6 ± 3.4%, P < 0.01). In PBCCs and vasculature, KL gene expression correlated inversely with pro-inflammatory markers and directly with anti-inflammatory markers. sKL serum levels presented similar associations with the expression levels of pro- and anti-inflammatory markers in PBCCs. The differences in KL expression levels in PBCCs and in serum sKL levels with respect to control group was even greater in those CVD patients with macroscopically observable atheromatous plaques. We conclude that promoter methylation-mediated downregulation of KL gene expression in PBCCs is associated with the pro-inflammatory status in atherosclerotic vascular disease.

Cardiovascular disease (CVD) is the leading cause of death worldwide. New therapeutic strategies are aimed to modulate the athero-inflammatory process that partially orchestrates underlying vascular damage. Peripheral blood circulating cells (PBCCs) include different immune cells with a central role in the development of the atherogenic inflammatory response. The anti-aging factor α-Klotho (KL) has been related to protective effects against CVD. KL is expressed in monocytes, macrophages and lymphocytes where it exerts anti-inflammatory effects. Our aim is to characterize the relationships between inflammatory markers and KL gene expression in PBCCs or serum levels of soluble KL (sKL) in atherosclerotic vascular disease. For this, we conducted a cross-sectional single center case-control study including 76 CVD patients and a control group of 16 cadaveric organ donors without medical antecedent or study indicating CVD. Vascular artery fragments, whole blood and serum samples were obtained during elective or organ retrieval surgery, respectively. Serum levels of sKL, TNFα and IL10 were measured. Gene expression levels of KL, TNF, IL10, NFKB1, DNMT1, and DNMT3A, and KL promoter methylation percentage in PBCCs were also determined. Histological and immunohistochemical analyses were employed to visualize atherosclerotic lesions and to measure IL10 and TNFα levels in vascular fragments.CVD patients presented higher values for pro-inflammatory markers in the vasculature, PBCCs and systemically compared to controls. In PBCCs, CVD group presented lower expression of KL gene compared to controls (56.4% reduction, P<0.001), which was accompanied by higher methylation of its promoter (34.1±4.1% vs. 14.6±3.4%, P<0.01) and higher gene expression of DNMT1 and DNMT3A (P<0.0001 for both). KL expression correlated inversely with pro-inflammatory markers in PBCCs and vasculature, but directly with anti-inflammatory markers. sKL serum levels presented similar associations with pro- and anti-inflammatory markers in PBCCs. KL expression in PBCCs and serum sKL levels were diminished in patients with macroscopically observable atheromatous plaques.We conclude that KL gene downregulation in PBCCs during atherosclerotic vascular disease, which is mediated by promoter methylation, is associated with the pro-inflammatory status developed in this disorder either in the vasculature or systemically.

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