In diabetic kidney disease (DKD), the link between diabetes and damage to podocytes is unclear. Mitochondrial dysfunction caused by lipid accumulation in podocytes might increase their susceptibility to injury, as reported by Alessia Fornoni, Sandra Merscher, Flavia Fontanesi and colleagues.
“We had previously shown that glomerular expression of phospholipid-transporting ATPase ABCA1 was lower in patients with DKD than in healthy controls, and that reducing Abca1 expression in mouse podocytes caused cholesterol accumulation,” explains Merscher. To assess the potential contribution of ABCA1 to kidney disease in the context of diabetes, the researchers induced a podocyte-specific deletion of Abca1 in diabetic ob/ob mice. The loss of Abca1 was accompanied by an increase in albuminuria and mesangial expansion, a reduction in the number of podocytes and podocyte foot processes, and increased cholesterol ester in the kidney.
The researchers also noted mitochondrial swelling in podocytes from Abca1–/– ob/ob mice. Targeting Abca1 with small interfering RNA in podocytes in vitro not only reduced oxidative phosphorylation and O2 consumption but also significantly increased cardiolipin content. Cardiolipin is a mitochondrial phospholipid that accumulates in cells from patients with loss-of-function ABCA1 mutations. Treating db/db diabetic mice with A30, a drug that increases ABCA1 expression, specifically reduced docosahexaenoic acid-rich cardiolipin species and significantly improved the kidney phenotype. Similarly, elamipretide, a drug that inhibits cardiolipin peroxidation, prevented DKD progression in ob/ob mice. “ABCA1 deficiency leads to cardiolipin accumulation and mitochondrial dysfunction,” adds Fontanesi. “These results are the first to link podocyte lipid metabolism to mitochondrial dysfunction in DKD.”
“Our next step is to identify and validate drugs that prevent cardiolipin peroxidation and/or esterified cholesterol accumulation,” remarks Fornoni. “We are designing a phase II clinical trial to test a small molecule inducer of ABCA1 in patients.”
Ducasa, G. M. et al. ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes. J. Clin. Invest. https://doi.org/10.1172/JCI125316 (2019)
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Wang, M. Lipids mediate podocyte damage. Nat Rev Nephrol 15, 594 (2019). https://doi.org/10.1038/s41581-019-0196-6