NLRP3 expression and urinary HSP72 in relation to biomarkers of inflammation and oxidative stress in diabetic nephropathy patients

Abstract

Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease. Nod-like receptors nucleotide-binding domain and leucine-rich repeat pyrin-3 domain (NLRP3) inflammasome displays a considerable role in the chronic inflammatory state observed in diabetic patients. Urinary heat shock protein 72 (uHSP72) is a sensitive and specific biomarker for the early detection of acute kidney injury. The aim of this study was to evaluate NLRP3 relative gene expression, its correlation with inflammatory and oxidative stress markers, and to assess the value of uHSP72 in the early detection of DN in type 2 diabetic patients with different degrees of DN. Forty-five type 2 diabetic patients: 15 normoalbuminuric, 15 microalbuminuric, 15 macroalbuminuric, in addition to 15 healthy controls were enrolled in this study. Clinical examination and routine laboratory investigations were performed. NLRP3 mRNA expression was assessed by real time polymerase chain reaction. Serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), interleukin 1β (IL-1β), and uHSP72 levels were estimated by enzyme-linked immunosorbent assay. Serum chitotriosidase (CHIT1) activity was examined. NLRP3 mRNA relative expression, serum levels of 8-OHdG, IL-1β, and uHSP72, in addition to CHIT 1 activity were significantly increased in the macroalbuminuric patient group as compared to control and the other two diabetic groups. Also, a significant positive correlation was documented between the previously mentioned parameters and urinary albumin/creatinine ratio, serum creatinine, and HbA1c. Multiple linear regression analysis using urinary albumin/creatinine ratio as dependent variable confirmed that uHSP72 and NLRP3 mRNA relative expression were the independent predictors of DN (β were 0.432 and 0.448 respectively, P < 0.001). Receiver operating characteristic analyses revealed that both NLRP3 mRNA relative expression and uHSP72 levels were useful biomarkers discriminating DN patients from patients with type 2 diabetes mellitus (AUC were 0.957 and 0.983, respectively). uHSP72 may be considered as a novel potential diagnostic biomarker for the early detection of DN. Moreover, these data support the pivotal role of NLRP3 in the development and progression of DN. © 2017 IUBMB Life, 69(8):623-630, 2017.

Heat Shock Proteins in Vascular Diabetic Complications: Review and Future Perspective

“…Therefore, HSPA/HSP70 may be beneficial in early DN because of its intracellular cytoprotective activity, but when albuminuria develops extracellular HSPA/HSP70 may contribute to the tubular-interstitial damage that is a key driver of DN progression. Consistent with this, a small study performed in patients with DM2 showed an association between urinary HSPA/HSP70 levels and albuminuria [ 112 ]. Moreover, serum HSPA/HSP70 levels were higher in DM2 patients with albuminuria [ 113 ] and polymorphisms of the HSPA/HSP70 gene were associated with DN in DM2 patients [ 114 ].…”

The Diagnostic and Prognostic Application of Heat Shock Proteins and their Post-Translational Modifications from Liquid Biopsies

“…Similar results were obtained in diabetic mice where TLR4 deletion or HSP70 inhibition reduced albuminuria and markers of inflammation and tubular injury [92]. Further supporting these findings, patients with T2DM with albuminuria showed higher serum HSP70 levels [93] as well as an association between urinary HSP70 levels and albuminuria [94]. Serum HSP70 was also found to be higher in patients with diabetic retinopathy, together with HIF-1α compared with subjects without [95] and correlated well with asymmetric dimethylarginine (ADMA) and C-reactive protein (CRP) levels in T2DM patients compared with healthy controls [96].…”

Interleukin-1β Inhibition for Chronic Kidney Disease in Obese Mice With Type 2 Diabetes

“…A low nephron number, as induced here by early uninephrectomy, further aggravates hyperfunction, and accelerates the demise of the remnant nephrons (42). Several studies have documented an increased expression of NLRP3 inflammasome components in renal parenchymal cells in experimental and human DKD and hence speculated on a role of IL-1β in CKD progression (18, 43–46). Indeed, Shahzad et al found db/db mice with T2DM to be protected from kidney disease by injecting human recombinant IL-1R antagonist anakinra (18).…”