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.