Myofibroblasts, regeneration or renal fibrosis--is there a decisive hint?

Abstract

Activated fibroblasts, denoted as myofibroblasts, express smooth muscle actin (SMA) and are considered key mediators of renal fibrosis. To identify and isolate these elusive cells, LeBleu et al. generated a new transgenic mouse model expressing a red fluorescent protein under the control of the alpha SMA promoter. Gene expression profiling from cultured myofibroblasts identified human epididymis protein 4 [HE4, also denoted whey acidic protein (WAP) four-disulphide core domain 2] as the most upregulated gene. Since the WAP domains are implicated in protease inhibition, the authors demonstrate the ability of recombinant HE4 to bind and inhibit a number of known proteases. To demonstrate an involvement of HE4 in disease pathology, the authors next showed that the neutralization of HE4 alleviates kidney fibrosis in murine disease models, i.e. 5/6 nephrectomy, unilateral ureteral obstruction and nephrotoxic serum-induced nephritis. Finally, they went on to verify the enhanced expression of HE4 in human fibrosis-associated fibroblasts in comparison to normal fibroblasts as well as in serum samples of patients with chronic kidney diseases. Thus, they conclude that HE4 can serve as a biomarker as well as a therapeutic target for the treatment of renal fibrosis.

Keywords: protease inhibitor; renal fibrosis; whey acidic protein (WAP) domain.