Biomedical Engineering Reference
In-Depth Information
nephritis, and indeed, there is a clear link between this disease and meprin
Different animal models have been used to elucidate the function of meprin a
and b in kidney pathology. The mouse strains C3H/He and CBA/Ca exclusively
express meprin b in proximal tubular cells, predominantly the inactive zymogen
form (promeprin b). 57,58 Interestingly, these mice developed less severe forms of
kidney disease after injury, compared to wild-type mice with normal meprin a
levels. This was the first indication for a role of meprin a in acute renal failure. 59
Indeed, further studies supported this observation. 55,60-63 Generally, it has been
found that both increased and decreased expression of meprins are associated
with kidney diseases.
The downregulation of meprins was predominantly found to be correlated
to chronic pathology, such as experimental diabetes (genetic or chemically
induced), adriamycin-induced nephropathy, hydronephrosis (unilateral
urethral ligation), in collagen IVA3 knockout mice that develop Alport's
syndrome, and in passive Hymann nephritis, anti-Thy 1.1 nephritis. 27,64-69
All these diseases incur necrosis and apoptosis, finally leading to fibrosis.
On the other hand, over-expression and/or mislocation of meprin a and b are
related to acute renal failure. It has been demonstrated that in mouse models of
ischemia, reperfusion injury, and acute renal failure, meprins were no longer
exposed at the apical brushborder membrane, but appear only at the baso-
lateral side of tubular epithelial cells. This redistribution of proteolytic activity
led to tissue damage by degradation of extracellular matrix proteins and to
generalized cytotoxicity. 70,71
Interestingly, the application of the hydroxamate inhibitor actinonin pre-
vented renal pathology in these mouse models. 59,63,72 Recently, Wang and
colleagues reported that actinonin has the ability to prevent not only the early
but also the late organ-damaging effects of sepsis, thus being a possible ther-
apeutic agent. 73 Actinon was previously described as a potent inhibitor for
human meprins; this will be discussed later, in relation to its potential template
for drug development. 54
The cytotoxic effect of active meprin was further demonstrated by meprin a
and b knockout mice. The lack of this protease significantly protected the
animals against renal ischemia-reperfusion injury and bladder inflamma-
tion. 55,74 Additionally, cultured tubular epithelia cells incubated with both
meprin a and b exhibited cytotoxity, which could be abolished by the addition
of actinonin and 1,10-phenanthroline. 63 Similar results were obtained using
cultured human keratinocytes. 39 Here, it could be clearly distinguished between
both meprin proteases, by demonstrating that only meprin b leads to cell death,
while meprin a rather supports cell proliferation.
A genetic study, analyzing the nucleotide sequence of the meprin b gene from
Pima Indians, revealed a link to diabetic nephropathy. 75 These authors found
nine significant single nucleotide polymorphisms (SNPs) in MEP1B which
might influence transcription or tracking of the enzyme. Diabetic nephro-
pathy finally results in fibrosis, a pathological condition also observed in der-
mal skin, when meprins are overexpressed by fibroblasts. 48
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