Mannose Receptor 2 Attenuates Renal Fibrosis

Abstract

Mannose receptor 2 (Mrc2) expresses an extracellular fibronectin type II domain that binds to and internalizes collagen, suggesting that it may play a role in modulating renal fibrosis. Here, we found that Mrc2 levels were very low in normal kidneys but subsets of interstitial myofibroblasts and macrophages upregulated Mrc2 after unilateral ureteral obstruction (UUO). Renal fibrosis and renal parenchymal damage were significantly worse in Mrc2-deficient mice. Similarly, Mrc2-deficient Col4a3 2/2 mice with hereditary nephritis had significantly higher levels of total kidney collagen, serum BUN, and urinary protein than Mrc2-sufficient Col4a3 2/2 mice. The more severe phenotype seemed to be the result of reduced collagen turnover, because procollagen III (a1) mRNA levels and fractional collagen synthesis in the wildtype and Mrc2-deficient kidneys were similar after UUO. Although Mrc2 associates with the urokinase receptor, differences in renal urokinase activity did not account for the increased fibrosis in the Mrc2-deficient mice. Treating wild-type mice with a cathepsin inhibitor, which blocks proteases implicated in Mrc2-mediated collagen degradation, worsened UUO-induced renal fibrosis. Cathepsin mRNA profiles were similar in Mrc2-positive fibroblasts and macrophages, and Mrc2 genotype did not alter relative cathepsin mRNA levels. Taken together, these data establish an important fibrosis-attenuating role for Mrc2-expressing renal interstitial cells and suggest the involvement of a lysosomal collagen turnover pathway.

Cellular and molecular mechanisms in kidney fibrosis

“…Nevertheless, MMP14, -1, and -13 all have well-described matrix-degrading functions at the cell surface, whereas MMP2 and -9 may play minor roles in extracellular degradation of fibrillar matrix (83,90,91). Evidence from models of fibrosis regression indicates reparative macrophages both enzymatically cleave and endocytose matrix, which is subsequently degraded by cathepsins in lysosomes (79,(92)(93)(94).…”

“…Mannose-C receptors (CD206 and Endo180) specifically endocytose collagen fragments in subsets of tissue macrophages (79,94) in kidney and skin disease, whereas discoidin-domainreceptor (DDR) family members bind fibrillar collagen but likely do not internalize it (95). Intriguingly, the plasma globulin MFGE8 has been reported to bind collagen via discoid domains and facilitate turnover by macrophages via an integrin-independent mechanism in lung disease (80).…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Whereas attempts have been made to modulate the activity of matrix-degrading enzymes, in particular of MMPs, as yet no useful therapies have emerged (21). Other approaches targeting ECM turnover might be successful as example shown for mannose receptor 2 (344). Another attractive therapeutic approach for fibrosis may be the interference with cellular recognition of the matrix.…”

Urinary tract obstruction in the mouse: the kinetics of distal nephron injury

“…[1][2][3][4] We have previously demonstrated that fetal obstruction in the human and primate kidney causes substantial medullary injury, including interstitial expansion, peritubular a smooth muscle actin (aSMA) collar formation, and collecting duct epithelial dysfunction. 1-3 Additional work is required to further identify how medullary and collecting duct injury contributes to and modulates the pathophysiology and progression of injury following obstruction.The rodent unilateral ureteric obstruction (UUO) models are the best-described models of urinary tract obstruction [5][6][7][8][9][10][11][12][13][14][15][16] and are widely used due to their ease of manipulation and the availability of transgenic animals. These models are predominantly postnatal models with much of the work focused on the role of the proximal convoluted tubule and on late time points in which the interstitial and fibrotic responses predominate.…”

“…The rodent unilateral ureteric obstruction (UUO) models are the best-described models of urinary tract obstruction [5][6][7][8][9][10][11][12][13][14][15][16] and are widely used due to their ease of manipulation and the availability of transgenic animals. These models are predominantly postnatal models with much of the work focused on the role of the proximal convoluted tubule and on late time points in which the interstitial and fibrotic responses predominate.…”