TNF-α and IL-1β Promote Renal Podocyte Injury in T2DM Rats by Decreasing Glomerular VEGF/eNOS Expression Levels and Altering Hemodynamic Parameters

Abstract

Purpose Diabetic nephropathy (DN) is a serious microvascular complication in those with type 2 diabetes mellitus (T2DM). Evidence confirms that serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the T2DM stage are proposed as prognostic markers for DN development, but it is unclear how they affect renal podocyte-associated nephrin and WT-1 expression. In the presence of podocyte injury, glomerular vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and hemodynamic parameters are dysregulated. The current research aimed to clarify the relationship of TNF-α and IL-1β with podocyte injury by altering VEGF/eNOS expression and hemodynamic parameters. Methods A high-fat diet/streptozotocin-induced DN rat model was established. Serum TNF-α and IL-1β levels were tracked in the pre-T2DM, T2DM and DN stages. In the DN stage, the mRNA and protein expression levels of renal TNF-α, IL-1β, VEGF, eNOS, nephrin and WT-1 were studied. Renal hemodynamic parameters, including peak systolic velocity, end-diastolic flow velocity and mean velocity were measured with a color Doppler ultrasound technique. Results Compared to those in the normal control (CTL) group, serum TNF-α and IL-1β levels increased significantly in the pre-T2DM stage (obesity, insulin resistance and hyperlipidemia), T2DM stage (hyperglycemia) and DN stage (abnormal renal functions) (all: P < 0.05) in the DN group. Serum TNF-α and IL-1β levels in the T2DM stage were significantly higher than those in the pre-T2DM stage (two: P < 0.05). Compared to the CTL group, renal nephrin, WT-1, TNF-α, IL-1β, eNOS and VEGF expression and hemodynamic parameters in the DN stage all showed significant differences separately (all: P < 0.05). Conclusion Increased serum and renal TNF-α and IL-1β levels played important roles in reducing renal nephrin and WT-1 expression levels, which may be related to the fact that the former affected renal VEGF/eNOS expression and blood flow parameters in the DN rats.

Drug pair of Cornus officinalis and Radix achyranthis bidentatae improves renal injury of hypertension by regulating metabolic reprogramming mediated by eNOS

“…From the perspective of metabolic reprogramming, this study elucidates the important role of eNOS in renal injury, providing us with new ideas for further prevention and treatment of hypertensive kidney injury from the perspective of metabolic reprogramming. Multiple studies [ [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] ] have found that eNOS is closely related to hypertension, kidney injury, etc. eNOS can make an decrease in PKM2, which is an important mediator for catalyzing glycolysis and increasing the conversion of phosphoenolpyruvate (PEP) to pyruvate.…”

The Molecular Mechanism of Renal Tubulointerstitial Inflammation Promoting Diabetic Nephropathy

“…47 Tumor necrosis factor (TNF) and its receptor (TNFR) are common inflammatory factors in DN and play a critical role in the pathogenesis of DN. [48][49][50] Increased expression of TNF and TNFR is detected in various kidney cells, including tubular epithelial cells and mesangial cells, following prolonged exposure to high glucose, ROS, AGEs, and lipopolysaccharides. Inflammatory mediators, such as IL1α and IL6, can also stimulate the expression of TNF-α and its receptors in kidney cells.…”