Knockout of toll-like receptor-2 attenuates both the proinflammatory state of diabetes and incipient diabetic nephropathy.

Abstract

OBJECTIVE:

Type 1 diabetes (T1DM) is a proinflammatory state and confers an increased risk for vascular complications. Toll-like receptors (TLR) could participate in diabetic vasculopathies. Whether TLR activation contributes to the proinflammatory state of T1DM and the pathogenesis of diabetic nephropathy remains unknown.

METHODS AND RESULTS:

We induced T1DM in TLR2 knockout mice (TLR2-/-) and wild-type littermates (C57BL/6J-WT) using streptozotocin (STZ). Fasting blood, peritoneal macrophages, and kidneys were obtained for flow cytometry, Western blot, microscopy, and cytokine assays at 6 and 14 weeks after induction of diabetes. Macrophage TLR2 expression and MyD88-dependent signaling were increased in diabetic mice (WT+STZ) compared with nondiabetic WT mice. These biomarkers were attenuated in diabetic TLR2-/- macrophages. WT+STZ mice showed increased kidney:body weight ratio due to cell hypertrophy, increased albuminuria, decreased kidney nephrin, podocin, and podocyte number and increased transforming growth factor-β and laminin compared with WT mice. Nephrin, podocin, and podocyte number and effacement were restored, and transforming growth factor-β and laminin levels were decreased in TLR2-/-+ STZ mice kidneys versus WT+STZ. Peritoneal and kidney macrophages were predominantly M1 phenotype in WT+STZ mice; this was attenuated in TLR2-/-+STZ mice.

CONCLUSIONS:

These data support a role for TLR2 in promoting inflammation and early changes of incipient diabetic nephropathy, in addition to albuminuria and podocyte loss.

• Authors: Sridevi Devaraj, Peter Tobias, Balakuntalam S Kasinath, Rajendra Ramsamooj, Alaa Afify, Ishwarlal Jialal
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 8 Pg. 1796-804 (Aug 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21617141 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Cytokines
• Inflammation Mediators
• NF-kappa B
• Tlr2 protein, mouse
• Toll-Like Receptor 2

Topics

• Animals
• Chemokines (blood)
• Cytokines (blood)
• Diabetes Mellitus, Experimental (immunology, pathology, physiopathology, prevention & control)
• Diabetic Nephropathies (immunology, pathology, physiopathology, prevention & control)
• Immunity, Innate
• Inflammation Mediators (physiology)
• Kidney (immunology, pathology, physiopathology)
• Macrophages (immunology, pathology, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Podocytes (pathology)
• Toll-Like Receptor 2 (antagonists & inhibitors, deficiency, genetics)