Inhibition of matrix metalloproteinases (MMPs) may provide a treatment for a rare inherited kidney disease, Alport syndrome, suggests a study by Michael Zeisberg et al. (PLoS Medicine 3, e100; 2006). But, as with stroke, the trick might be when to apply the drugs (see “Remodeling after stroke”, Nat. Med. 12, 390–391; 2006).
The disease is due to mutations in genes encoding the chains of type IV collagen. These mutations have been proposed to increase susceptibility of the basement membrane of the glomerulus, a filtering structure, to digestion by MMPs. The new findings support that view.
In a mouse model of the disease, the researchers found that inhibition of MMPs early in the disease, before the buildup of proteins in the urine, eased symptoms. Inhibition of multiple MMPs may be crucial, as mice deficient in only one MMP can upregulate another MMP (shown is a glomerulus in a MMP-9–deficient mouse. MMP-2, in green, is upregulated. Extracellular matrix is in red). In contrast, inhibition of MMPs at later stages of disease exacerbated symptoms.
The researchers propose that at early stages MMPs help break down the the basement membrane, and that at later stages they may help remove extracellular matrix associated with scarring and fibrosis.
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Schubert, C. Remodeling in the kidney. Nat Med 12, 391 (2006). https://doi.org/10.1038/nm0406-391