TLR4 activation promotes podocyte injury and interstitial fibrosis in diabetic nephropathy.
Toll like receptor (TLR) 4 has been reported to promote inflammation in diabetic nephropathy. However the role of TLR4 in the complicated pathophysiology of diabetic nephropathy is not understood. In this study, we report elevated expression of TLR4, its endogenous ligands and downstream cytokines, chemokines and fibrogenic genes in diabetic nephropathy in WT mice with streptozotocin (STZ) diabetes. Subsequently, we demonstrated that TLR4-/- mice were protected against the development of diabetic nephropathy, exhibiting less albuminuria, inflammation, glomerular hypertrophy and hypercellularity, podocyte and tubular injury as compared to diabetic wild-type controls. Marked reductions in interstitial collagen deposition, myofibroblast activation (α-SMA) and expression of fibrogenic genes (TGF-β and fibronectin) were also evident in TLR4 deficient mice. Consistent with our in vivo results, high glucose directly promoted TLR4 activation in podocytes and tubular epithelial cells in vitro, resulting in NF-κB activation and consequent inflammatory and fibrogenic responses. Our data indicate that TLR4 activation may promote inflammation, podocyte and tubular epithelial cell injury and interstitial fibrosis, suggesting TLR4 is a potential therapeutic target for diabetic nephropathy.
Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Jin
J
Ma
Renal Medicine and Transplant Research Group, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Steven J
SJ
Chadban
Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Cathy Y
CY
Zhao
Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Xiaochen
X
Chen
Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Tony
T
Kwan
Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Usha
U
Panchapakesan
Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Carol A
CA
Pollock
Renal Medicine and Transplant Research Group, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Huiling
H
Wu
D000704:Analysis of Variance; D000818:Animals; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000503:physiopathology*; D024202:Electrophoretic Mobility Shift Assay; D005355:Fibrosis / Q000503:physiopathology*; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050199:Podocytes / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D003094:Collagen