Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria

Alchiede Simonato, Laura Cappuccino, Mariano Mij, Fabio Gianiorio, Gennaro Salvidio, Daniela Verzola, Elena D'Amato, Francesca Viazzi, Alchiede Simonato, Barbara Villaggio, Giacomo Garibotto

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

Toll-like receptor 4 (TLR4), a component of the innate immune system, is recognized to promote tubulointerstitial inflammation in overt diabetic nephropathy (DN). However, there is no information on immune activation in resident renal cells at an early stage of human DN. In order to investigate this, we studied TLR4 gene and protein expression and TLR4 downward signaling in kidney biopsies of 12 patients with type 2 diabetes and microalbuminuria, and compared them with 11 patients with overt DN, 10 with minimal change disease (MCD), and control kidneys from 13 patients undergoing surgery for a small renal mass. Both in microalbuminuria and in overt DN, TLR4 mRNA and protein were overexpressed 4- to 10-fold in glomeruli and tubules compared with the control kidney and in MCD. In addition, NF-κB signaling was about fourfold higher in the glomeruli. TNF-α, IL6, CCR2, CCL5, and CCR5 mRNAs were markedly (about three- to fivefold) upregulated in microdissected glomeruli. While IL6, CCL2 and CCR5-mRNA, and CD68 were overexpressed in the tubulointerstitial compartment in clinical DN, they were not expressed in microalbuminuria. In a 6-year follow-up of microalbuminuric patients, glomerular TLR4 gene expression was associated with the subsequent loss of kidney function. Thus, innate immunity is activated in the glomeruli of patients with diabetic microalbuminuria. Enhanced TLR4 signaling may contribute to the progression occurring after the incipient, microalbuminuric form of nephropathy evolves to overt disease.
Original languageEnglish
Pages (from-to)1229-1243
Number of pages15
JournalKidney International
Volume86
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Nephrology

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