Targeting Early Renal Dysfunction in Metabolic Impairment: Modulation of Peri-Renal Adipose Thromboinflammation

Abstract

Endothelial dysfunction has been postulated to take a leading role in the pathogenesis of diabetic nephropathy. Developing evidence suggest that this dysfunction progresses early on prior to the diagnosis of diabetes, and is linked to metabolic syndrome. Prior research showed that peri-renal adipose tissue (PRAT) expansion in obesity and metabolic syndrome was associated with kidney function deterioration without a clear mechanism. Our laboratory recently reported that a prediabetic rat model showed proteinuria and hyperfiltration together with renovascular endothelial dysfunction triggered by PRAT inflammation. A large body of evidence implicates increased thrombin and factor Xa activity in inflamed adipose tissue. These factors evoke further adipose inflammation through the activation of protease-activated receptors precipitating a vicious cycle. As such, Factor Xa inhibition by rivaroxaban treatment will interrupt adipose/thromboinflammation leading to the amelioration of PRAT-induced renal dysfunction. To study this dysfunction, a non-obese prediabetic rat model was used. Rats received a two-week rivaroxaban treatment. Kidney functional parameters including urinary protein levels and glomerular filtration rate were determined for control and pre-diabetic rats with or without rivaroxaban treatment. After sacrifice, renovascular endothelial function was assessed in isolated perfused kidneys. Signs of renal structural impairment was assessed using histopathological techniques. The expression levels of the inflammatory mediator were determined in PRAT. The high caloric diet lead to a significant increase in serum triglyceride and a significant increase in fat:lean ratio without an increase in body weight in HC-fed rats with and without rivaroxaban treatment compared to the control group. PRAT inflammation measured by blotting for IL-1  showed a significant decrease in Riva treated group compared to the HC-fed group. In addition, oxidative stress in both PRAT and kidney was significantly decreased with Riva treatment compared to the HC-fed rats suggesting a better amelioration of the pro-inflammatory milieu. Moreover, amelioration of renal structural and functional parameters were recorded as enhanced eGFR and less proteinuria together with better renovascular endothelial feedback to increased sheer stress and PE constriction. The mediators involved in this feedback were assessed by adding prostaglandins (PG), endothelial nitric oxide (eNOS) and epoxyeicosatrienoic acids (EETs) blockers revealing the decreased involvement of PG and eNOS and increased involvement of EET in the renovascular relaxation of HC-fed rats and the restoration of the normal mediator action in Riva treated group. In conclusion, rivaroxaban treatment reverses PRAT inflammation and is associated with an amelioration of renal structural, functional and endothelial impairment without altering metabolic parameters.