Renal fibrosis is a common pathological feature of chronic kidney disease and has been linked to the accumulation of lipids in the kidney. Now, Carlos Fernández-Hernando, Santiago Lamas and colleagues show that microRNA-33 (miR-33), known for regulating lipid metabolism, also affects the development of fibrosis in the kidney.
“Altered fatty acid oxidation (FAO) is important in kidney fibrosis and our previous work showed that miR-33 regulates FAO and cholesterol metabolism,” explains Fernández-Hernando. In the folic acid-induced neprophathy (FAN) mouse model of kidney fibrosis, Mir33–/– mice had lower expression of fibrosis markers (α-smooth muscle actin, fibronectin and collagen) and lower levels of blood urea nitrogen (BUN) and creatinine than wild-type (WT) mice. Reconstituting the haematopoietic cell compartment of WT mice with Mir33–/– bone marrow did not improve fibrosis in the FAN model.
Oxygen consumption rate was enhanced in Mir33–/– renal tubular epithelial cells but not in the presence of etomoxir, an inhibitor of carnitine palmitoyltransferase 1 (CPT1), which is an FAO regulator and a target of miR-33. In Mir33–/– mice, CPT1A levels increase after FAN.
The researchers also used pH low insertion peptides (pHLIPs) to deliver a miR-33 inhibitor to mice. pHLIPs deliver their cargo specifically to acidic environments and are known to accumulate in the kidney — in vitro, fluorescent pHLIPs accumulated in mouse primary renal tubular cells. In the FAN model, mice treated with anti-miR-33pHLIP had higher CPT1A, improved kidney fibrosis, and lower BUN and creatinine levels compared with untreated mice. “miR-33 regulates lipid metabolism in the pathological setting of kidney fibrosis,” concludes Lamas.
“Next, we want to explore how different miR-33 targets contribute to kidney fibrosis,” explains Fernández-Hernando. “Selective microRNA inhibition in the kidney with the pHLIP system should also be explored for therapeutic use,” adds Lamas.
Price, N. L. et al. Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis. JCI Insight https://doi.org/10.1172/jci.insight.131102 (2019)
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Wang, M. Kidney miR-33 controls fatty acid oxidation. Nat Rev Nephrol 16, 66 (2020). https://doi.org/10.1038/s41581-019-0228-2