Up-regulation in the kidney and its genetic polymorphism of MUC20, a regulator of Met signaling cascade, in patients with IgA nephropathy

Abstract

MUC20, a novel mucin protein highly expressed in kidney, was isolated as an up-regulated gene in renal tissues of patients with IgA nephropathy (IgAN) ( J Biol Chem 279:1968, 2004). Functional analyses of MUC20 have demonstrated its role as a negative regulator of hepatocyte growth factor (HGF)-induced Grb2-Ras pathway. The C-terminus of MUC20 associates with the multifunctional docking site of Met, preventing Grb2 recruitment to Met and thus attenuating HGF-induced proliferation and matrix metalloproteinase expression ( Mol Cell Biol 24:7456, 2004). In addition, it has been suggested that the oligomerization of MUC20, caused by its overproduction or some other unknown factor(s), which leads to this association with Met. Interestingly, in human MUC20, the repeat numbers of the extracellular tandem domain, which may have an influence on the oligomerization, showed a divergence, with two to six repeat types in several human cell lines. In this study, to clarify the role of MUC20 in human kidney diseases, we analyzed the expression of MUC20 in kidney tissues of patients with IgAN by in situ hybridization. We also investigated the possible association of the tandem repeat polymorphism of MUC20 with renal survival in 236 patients with histologically proven IgAN. In normal kidneys, the expression of MUC20 was confined to the distal tubules, where Met was colocalized by immunohsitochemistry. In addition, glomerular podocytes and the parietal epithelial cells lining Bowman's capsule demonstrated positive expression of MUC20. In renal tissues of IgAN, up-regulation of MUC20 expression in proximal tubules, as well as in distal tubules, was observed. By Kaplan-Meier analysis, the prognosis of IgAN patients with five or six of tandem repeat of MUC20 ( N = 130) was significantly better than those without ( N = 106, log-rank, χ 2 = 10.51) ( P = 0.0012). The tandem repeat polymorphism of MUC20 was an independent risk factor for the progression of renal dysfunction even after adjusting for other clinical risk factors, including hypertension, urinary protein excretion of more than 1.0 g/day, and no administration of renin angiotensin system inhibitors. This study supports the role of MUC20 in regulating the Met signaling cascade, which is implicated not only in renal development and maintenance of kidney functions but also in tubular repair and regeneration under pathological conditions in human glomerulonephritis. The tandem repeat polymorphism in MUC20, which may directly affect its oligomerization and binding to Met, is associated with the renal prognosis of IgAN. Factors that regulate the function of MUC20 may be useful therapeutic agents for progression of renal injury.