Urinary podocyte-associated mRNA levels correlate with proximal tubule dysfunction in early diabetic nephropathy of type 2 diabetes mellitus

Abstract

AimThe study assessed mRNA expression of podocyte-associated molecules in urinary sediments of patients with type 2 diabetes mellitus (DM) in relation to urinary podocytes, biomarkers of podocyte injury and of proximal tubule (PT) dysfunction.MethodsA total of 76 patients with type 2 DM and 20 healthy subjects were enrolled in a cross-sectional study, and assessed concerning urinary podocytes, urinary mRNA of podocyte-associated genes, urinary biomarkers of podocyte damage and of PT dysfunction.ResultsWe found significant differences between urinary mRNA of podocyte-associated molecules in relation with albuminuria stage. In multivariable regression analysis, urinary mRNA of nephrin, podocin, alpha-actinin-4, CD2-associated protein, glomerular epithelial protein 1 (GLEPP1), ADAM 10, and NFκB correlated directly with urinary podocytes, albuminuria, urinary alpha1-microglobulin, urinary kidney-injury molecule-1, nephrinuria, urinary vascular endothelial growth factor, urinary advanced glycation end-products (AGE), and indirectly with eGFR (p < 0.0001, R2 = 0.808; p < 0.0001, R2 = 0.825; p < 0.0001, R2 = 0.805; p < 0.0001, R2 = 0.663; p < 0.0001, R2 = 0.726; p < 0.0001, R2 = 0.720; p < 0.0001, R2 = 0.724).ConclusionsIn patients with type 2 DM there is an association between urinary mRNA of podocyte-associated molecules, biomarkers of podocyte damage, and of PT dysfunction. GLEPP1, ADAM10, and NFκB may be considered additional candidate molecules indicative of early diabetic nephropathy. AGE could be involved in this association.

Renal ADAM10 and 17: Their Physiological and Medical Meanings

“…ADAM10 and 17 are closely correlated with renal injuries including excess inflammation and tubular cell destruction. In addition to their substrates, ADAM10 and 17 per se are also important biomarkers of renal dysfunctions, such as early DN ( Petrica et al, 2017 ; Gutta et al, 2018 ). Furthermore, many efforts have been made to develop strategies to block ADAM10 and 17 activities involving small molecules and monoclonal antibodies (Figure 2 ).…”

Are the Therapeutic Effects of Huangqi (Astragalus membranaceus) on Diabetic Nephropathy Correlated with Its Regulation of Macrophage iNOS Activity?

“…Recent research showed that there are significant differences between urinary mRNA of podocyte-associated molecules in relation with albuminuria stage [ 4 ], and the activation of macrophages causes podocyte damage in DN [ 5 ]. Macrophages in a resting state appear to have no obvious effect on renal injury, and macrophages in an activated state are very important to the disease progression.…”

Ramipril and resveratrol co‐treatment attenuates RhoA/ROCK pathway‐regulated early‐stage diabetic nephropathy‐associated glomerulosclerosis in streptozotocin‐induced diabetic rats

“…Encouraging patients with early-stage DN to start necessary treatments is difficult because of the weak diagnostic markers for this condition, such as hyperfiltration (Table 1) to be related to advanced glycation end-product intervention in normoalbuminuria. 24 This finding indicates that DN should not be considered a chronic disease, and early-stage DN may be initiated over a short period of time with DM.…”

“…In this work, Masson's trichrome staining revealed that the positive/negative glomerulosclerosis ratio exhibits a similar pattern to serum glucose and serum HbA1c expression in an STZ‐induced DM animal model within 45 days. Recently, urinary nephrin and urinary vascular endothelial growth factor processing in early DN were suggested to be related to advanced glycation end‐product intervention in normoalbuminuria . This finding indicates that DN should not be considered a chronic disease, and early‐stage DN may be initiated over a short period of time with DM.…”