Diabetes induced renal complications by leukocyte activation of nuclear factor κ-B and its regulated genes expression

Abstract

Type 2 diabetes mellitus (T2D) is a metabolic disorder characterized by inappropriate insulin function. Despite wide progress in genome studies, defects in gene expression for diabetes prognosis still incompletely identified. Prolonged hyperglycemia activates NF-κB, which is a main player in vascular dysfunctions of diabetes. Activated NF-κB, triggers expression of various genes that promote inflammation and cell adhesion process. Alteration of pro-inflammatory and profibrotic gene expression contribute to the irreversible functional and structural changes in the kidney resulting in diabetic nephropathy (DN). To identify the effect of some important NF-κB related genes on mediation of DN progression, we divided our candidate genes on the basis of their function exerted in bloodstream into three categories (Proinflammatory; NF-κB, IL-1B, IL-6, TNF-α and VEGF); (Profibrotic; FN, ICAM-1, VCAM-1) and (Proliferative; MAPK-1 and EGF). We analyzed their expression profile in leukocytes of patients and explored their correlation to diabetic kidney injury features. Our data revealed the overexpression of both proinflammatory and profibrotic genes in DN group when compared to T2D group and were associated positively with each other in DN group indicating their possible role in DN progression. In DN patients, increased expression of proinflammatory genes correlated positively with glycemic control and inflammatory markers indicating their role in DN progression. Our data revealed that the persistent activation NF-κB and its related genes observed in hyperglycemia might contribute to DN progression and might be a good diagnostic and therapeutic target for DN progression. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers.

Keywords: 2hPPBG, 2 h post prandial blood glucose.; ACR, albumin creatinine ratio; BMI, body mass index.; DBP, Diastolic blood pressure.; DN, diabetic nephropathy.; FBS, fasting blood glucose.; FN; HDL, High density lipoprotein-cholesterol.; HbA1c, Glycosylated hemoglobin.; ICAM-1; IL-1β; IL-6; LDL, Low density lipoprotein-cholesterol.; M, male, F, female.; NF-κB; S.Cr, serum creatinine.; SBP, Systolic blood pressure.; T2D, type 2 diabetes mellitus without nephropathy.; TC, total cholesterol.; TGs, Triglyceride.; TNF-α; VCAM-1; VEGF; VLDL, Very low-density lipoprotein.; e-GFR, estimated glomerular filtration rate..

Fig. 3.1

Samples of leukocyte total RNA were assessed using Formaldehyde/ Formamide denaturant. Lane 1: RNA from control subject; Lane 2: RNA sample from T2D subject. Lanes 3: RNA sample from DN subject. The 28S and 18S ribosomal RNA bands are visible in the gel photo implying that the RNA samples are intact.