Circulating Tumor Necrosis Factor Receptors: A Potential Biomarker for the Progression of Diabetic Kidney Disease

Abstract

Despite considerable advancements in medicine, the optimal treatment for chronic kidney disease (CKD), especially diabetic kidney disease (DKD), remains a major challenge. More patients with DKD succumb to death due to cardiovascular events than due to progression to end-stage renal disease (ESRD). Moreover, patients with DKD and ESRD have remarkably poor prognosis. Current studies have appreciated the contribution of inflammation and inflammatory mediators, such as tumor necrosis factor (TNF)-related biomarkers, on the development/progression of DKD. The present review focuses on molecular roles, serum concentrations of TNF receptors (TNFRs), and their association with increased albuminuria, eGFR decline, and all-cause mortality in diabetes. Experimental studies have suggested that DKD progression occurs through the TNFα–TNFR2 inflammatory pathway. Moreover, serum TNFR levels were positively associated with albuminuria and negatively associated with estimated glomerular filtration rate (eGFR), while circulating levels of TNFRs exhibited an independent effect on all-cause mortality and eGFR decline, including ESRD, even after adjusting for existing risk factors. However, their precise function has yet to be elucidated and requires further studies.

Intestinal SIRT1 Deficiency-Related Intestinal Inflammation and Dysbiosis Aggravate TNFα-Mediated Renal Dysfunction in Cirrhotic Ascitic Mice

“…Meanwhile, TNFR1 is highly expressed in the renal proximal tubule and collecting duct, TNFR1 activation reduces renal blood flow (RBF) and glomerular filtration rate (GFR) [ 45 , 46 ]. In patients with diabetic kidney disease, serum TNFR levels are positively associated with estimated glomerular filtration rate (eGFR) decline and disease severity [ 47 , 48 ]. In SIRT1 IEC-KO BDL-cirrhotic mice the detrimental renal effects of intestinal SIRT1 deficiency, including further decrease in RBF and GFR, occurred through the simultaneous upregulation of intestinal and renal TNFα-TNFR1 cascades ( Supplement Figure S5 ).…”

Circulating levels of soluble tumor necrosis factor receptor 2 are associated with progressive diabetic kidney disease in patients with type 2 diabetes mellitus

“…In addition to the traditional risk factors, such as poor glycemic 15 or blood pressure 16 control, chronic lowgrade in ammation plays an important role in the development of DKD. 9 Activation of TNF pathways is associated with renal function decline in patients with chronic kidney disease. 17 Tumor necrosis factor alpha is involved in the signal transduction pathways by interacting with two types of membrane receptors: tumor necrosis factor receptor (TNFR) 1 and TNFR2.…”

“…19 Tumor necrosis factor receptor 1 and TNFR2 induce shared and distinctive signalling pathways that lead to apoptosis, proliferation, and in ammation. 9 Both membrane-bound receptors TNFR1 and TNFR2 can be cleaved by the metalloproteinase and released as circulating polypeptides, soluble TNFR1 (sTNFR1) and sTNFR2. 20 Higher serum sTNFR2 concentrations have been proven to be associated with increased risks of renal function decline or ESRD in patients with type 2 diabetes.…”

“…In ammation has emerged as an important mechanism in the pathogenesis of DKD. 9 Tumor necrosis factor alpha (TNFα) is an in ammatory cytokine produced by endothelial cells, fat, and immune cells.…”

New Potential Biomarkers for Chronic Kidney Disease Management—A Review of the Literature

“…The overexpression of other pro-inflammatory cytokines, such as interleukin-8 (IL-8) and interleukin-18 (IL-18), has also been linked to renal function decline [113,115,116]. Likewise, soluble TNF receptors 1 and 2 (sTNFR1 and sTNFR2) showed an important role in the progression of atherosclerosis and kidney diseases [117,118].…”