Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria.
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.
1] Nephrology Division, Department of Internal Medicine, Genoa University, Genoa, Italy [2] IRCCS AOU San Martino-IST, Genoa, Italy.
Daniela
D
Verzola
1] Nephrology Division, Department of Internal Medicine, Genoa University, Genoa, Italy [2] IRCCS AOU San Martino-IST, Genoa, Italy.
Laura
L
Cappuccino
Nephrology Division, Department of Internal Medicine, Genoa University, Genoa, Italy.
Elena
E
D'Amato
Nephrology Division, Department of Internal Medicine, Genoa University, Genoa, Italy.
Barbara
B
Villaggio
Nephrology Division, Department of Internal Medicine, Genoa University, Genoa, Italy.
Fabio
F
Gianiorio
Nephrology Division, Imperia Hospital, Imperia, Italy.
Mariano
M
Mij
1] IRCCS AOU San Martino-IST, Genoa, Italy [2] Clinica Urologica "L. Giuliani" DISC, Genoa, Italy.
Alchiede
A
Simonato
1] Nephrology Division, Department of Internal Medicine, Genoa University, Genoa, Italy [2] IRCCS AOU San Martino-IST, Genoa, Italy.
Francesca
F
Viazzi
IRCCS AOU San Martino-IST, Genoa, Italy.
Gennaro
G
Salvidio
1] Nephrology Division, Department of Internal Medicine, Genoa University, Genoa, Italy [2] IRCCS AOU San Martino-IST, Genoa, Italy.
Giacomo
G
Garibotto
D000419:Albuminuria / Q000276:immunology / Q000378:metabolism*; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D015415:Biomarkers / Q000737:chemistry; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000276:immunology / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007678:Kidney Glomerulus / Q000737:chemistry*; D007684:Kidney Tubules / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D009402:Nephrosis, Lipoid / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D018946:Chemokine CCL5; D015850:Interleukin-6; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C483024:CCL5 protein, human; C515334:CCR2 protein, human; C584933:CCR5 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule