New data from Lina Shehadeh and colleagues suggest that osteopontin is a potential therapeutic target for Alport syndrome. Increased expression of this phosphoprotein has previously been reported in various diseases, including nephrotic syndrome. “At basal levels, osteopontin is mainly expressed in the bones and to some extent in the kidneys and gall bladder,” says Shehadeh. “However, when there is stress or inflammation, osteopontin expression becomes exponentially high in the diseased organ and in the circulation.”

To investigate the role of osteopontin in Alport syndrome, the researchers used the Col4a3–/– mouse model of this disease. They report increased expression of osteopontin, dynamin 3 and the low-density lipoprotein receptor (LDLR) as well as cholesterol accumulation and dysmorphic mitochondria in the kidney tubules of these mice compared with wild-type controls. Heterozygous deletion of osteopontin increased lifespan and reduced renal, ocular and cochlear pathologies, cholesterol accumulation and the expression of dynamin 3 and LDLR in Col4a3–/– mice.

Further investigations using human renal epithelial cells demonstrated that osteopontin induces the expression of dynamin 3, which in turn upregulates LDLR, resulting in increased cholesterol influx. Dynamin 3 overexpression also resulted in impaired mitochondrial respiration in renal epithelial cells, suggesting a causative role of increased dynamin 3 levels in mitochondrial dysfunction in Alport syndrome.

“Our findings identify a new pathway that may be responsible for renal cholesterol accumulation and metabolic dysfunction in Alport syndrome,” concludes Shehadeh. “Importantly, the osteopontin–dynamin 3–LDLR pathway may also have a role in other degenerative diseases in which cholesterol and/or lipid toxicity are prominent, such as atherosclerosis and cancer.”