A protein's role in progressive renal disease

Focal segmental glomerulosclerosis (FSGS) made a brief media splash last year when a kidney transplant forced NBA superstar Alonso Mourning into early retirement. Mourning's condition elicited a flood of calls from fans offering their kidneys, but most people with kidney disease are not so lucky.

Some 56,000 patients await transplants; many have waited over five years. FSGS, which underlies about 25% of the 60,000 kidney-related deaths each year, causes progressive kidney failure.

FSGS commonly occurs as an outgrowth of various primary disorders, including obesity, HIV infection, diabetes, and hypertension. Though it's not clear what causes FSGS, this form of renal pathology is becoming more common.

By using the genes underlying inherited forms of FSGS as probes, scientists hope to uncover the mechanisms that unleash the disease and to find ways to stem the damage.

Mutations in the ACTN4 gene, which encodes a protein called a-actinin-4, cause an inherited form of FSGS. The protein normally remodels actin filaments, the primary structural component of muscle and cytoskeleton.

Having a single mutated copy of the gene can cause FSGS in humans, though it is unclear how. In this issue of PLoS Biology, Martin Pollak and his colleagues at Brigham and Women's Hospital at Harvard Medical School use a three-pronged approach to figure out how the defective protein wreaks renal havoc and how these physiological changes lead to FSGS.

Using biochemical analysis, cell-based studies, and a newly developed "knockin" mouse model, the researchers report two possible mechanisms of initiating disease.

Aggregation of a-actinin-4 and the toxic affects of aggregation could injure kidney cells, or loss of a-actinin-4 function caused by rapid degradation of the protein could produce injury.

Pollak and colleagues argue that both factors likely play a role.


Contact: Susanne DeRisi
Public Library of Science

Page: 1

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