Uteroglobin: Physiological role in normal glomerular function uncovered bytargeted disruption of the uteroglobin gene in mice

Blastokinin or uteroglobin (UG) is an evolutionarily conserved, steroid-ind ucible, homodimeric, multifunctional, secreted protein with potent immunomo dulatory/antiinflammatory properties. Recently, a UG-receptor expressed on several malignant and normal cell types has been characterized. Although th e biochemistry, structural, and molecular biology of UG have been extensive ly studied, its physiological function(s), until recently, remained unknown . By generating UG-null (UG(-/-)) mice, we determined that an essential rol e of UG is to prevent severe renal disease caused by an abnormal deposition of predominantly multimeric fibronectin (Fn) and collagen in the glomerulu s. The molecular mechanisms by which UG prevents this disease in control (U G(+/+)) mice, at least in part, is attributable to its high-affinity bindin g to Fn and the formation of Fn-UG heteromers, which counteract both Fn-Fn and Fn-collagen interactions, required for abnormal tissue deposition. In a ddition, by inhibiting secretory phospholipase A(2)(sPLA(2)) activity and d ecreasing the level of lysophosphatidic acid (LPA), UG may indirectly preve nt the activation of integrins leg, (alpha(5)beta(1)) that enhance abnormal tissue deposition of Fn. The mechanism(s) of UG action is likely to be eve n more complex, because it also functions through a receptor-mediated pathw ay that has not yet been clearly defined. Nevertheless, the UG gene-knockou t mice provide a valuable animal model for investigation of human glomerulo pathies in general and familial Fn-deposit glomerulopathy in particular. (C ) 1998 by the National Kidney Foundation, Inc.