Type 1 diabetes mellitus (T1DM) is a pro-inflammatory state with increased toll-like receptor (TLR) activity. Inflammation is crucial in diabetic nephropathy (DN). We tested the effect of global deficiency of TLR4 on renal inflammation, fibrosis and podocytopathy using control (C) and streptozotocin (STZ) induced diabetic wildtype (WT) and TLR4-knockout (TLR4KO) mice.Following STZ treatment, mice were euthanized at 17weeks and plasma and kidneys collected.Compared to C, STZ-WT mice had significantly increased macrophage and TLR4 immunostaining in kidney, significant increases in MyD88, Interferon Regulatory Factor-3, NFKappaB activity, TNF-Alpha, IL-6, and MCP-1; all these were significantly decreased in the STZ-TLR4KO compared to STZ-WT mice. Compared to C, there were significant increases in fibrosis markers (collagen 4, and transforming growth factor-beta) in STZ-WT which were significantly decreased in the STZ-TLR4KO versus STZ-WT. Podocyte numbers and podocin were decreased in the STZ-WT versus C and increased in the STZ-TLR4KO mice.Global genetic deficiency of TLR4 also ameliorates renal inflammation, fibrosis and podocytopathy and could be important in DN.