We have previously shown that stanniocalcin-1 (STC1) inhibits the transendothelial migration of macrophages and T cells, suppresses superoxide generation in macrophages, and attenuates macrophage responses to chemoattractants. To study the effects of STC1 on inflammation, in this study we induced a macrophage-and T-cell-mediated model of anti-glomerular basement membrane disease in STC1 transgenic mice, which display elevated serum STC1 levels and preferentially express STC1 in both endothelial cells and macrophages. We examined the following parameters both at baseline and after anti-glomerular basement membrane antibody treatment: blood pressure; C 3a levels; urine output; proteinuria; blood urea nitrogen; and kidney C 3 deposition, fibrosis, histological changes, cytokine expression, and number of T cells and macrophages. Compared with wild-type mice, after anti-glomerular basement membrane treatment STC1 transgenic mice exhibited: i) diminished infiltration of inflammatory macrophages in the glomeruli; ii) marked reduction in crescent formation and sclerotic glomeruli; iii) decreased interstitial fibrosis; iv) preservation of kidney function and lower blood pressure; v) diminished C 3 deposition in the glomeruli; and vi) reduced expression of macrophage inhibitory protein-2 and transforming growth factor-2 in the kidney. Compared with baseline , wild-type mice , but not STC1 transgenic mice , had higher proteinuria and a marked reduction in urine output. STC1 had minimal effects , however , on both T-cell number in the glomeruli and interstitium and on cytokine expression characteristic of either TH1 or TH2 activation. These data suggest that STC1 is a potent anti-inflammatory and renal protective protein. Stanniocalcin-1 (STC1) is a 25-kDa homodimeric glycoprotein hormone involved in calcium regulation in bony fish, 1 in which elevation of serum calcium triggers the release of STC1 from the corpuscles of Stannius, 2 organs associated with the kidneys.3 On circulation in the gill and intestine, STC1 inhibits calcium influx from the aquatic environment to the blood to maintain stable concentrations of calcium in the blood. 4 Mammalian STC1 mRNA is ubiquitously expressed, and the highest levels of STC1 expression are found in the ovary, kidney, prostate, and thyroid. [5][6][7] It was previously suggested that STC1 protein does not circulate in the blood of mammals 8 except during pregnancy and lactation 9 ; however, recent data suggest that mammalian STC1 is blood-borne , attached to a soluble protein. 10 The cellular distribution of STC1 mRNA and protein in mammalian organs is not always parallel. In the kidney for example, in situ hybridization revealed restricted expression of STC1 mRNA in the cortical and medullary collecting ducts, whereas the protein is detected along the entire nephron. 11,12 Similarly, the distribution of STC1 mRNA does not parallel the distribution of the protein in cellular elements of the ovary and pregnant uterus.