Annexin 1 Mimetic Ac2-26 Holds Promise for the Treatment of Diabetic Nephropathy.

In this issue of Diabetes, Wu et al. (1) report that in a high-fat diet/streptozotocin–induced diabetes model, global annexin 1 (ANAX1) deletion exacerbates diabetic nephropathy (DN), as indicated by increased albuminuria and macrophage infiltration, increased glomerular size, mesangial expansion, glomerular basement membrane thickness, and foot process effacement, increased tubulointerstitial injury, and fibrosis. They also detected lipid accumulation and mitochondrial abnormalities in the proximal tubule epithelial cells. RNA-sequencing analysis revealed a role of ANAX1 in lipid metabolism in the HFD/STZ-induced DN mice. Using a human immortalized proximal tubule epithelial cell line, HK-2 cells, they found that ANAX1 knockdown impaired mitochondrial fatty acid oxidation via a FPR2/AMPK/PPARα/CPT2b signaling pathway, leading to reduced intracellular lipid accumulation. ANAX1 knockdown also aggravated the lipid disorders in podocytes. Finally, administration of Ac2-26, an ANAX1 mimetic, ameliorated renal lipotoxicity in both diabetic ANAX1 knockout mice and diabetic db/db mice. In a recent study, the same group also reported that ANAX1 overexpression ameliorated DN and that ANAX1 expression is upregulated and correlates with kidney function and outcomes from data from a cohort of patients with diabetes (1,2).

ANAX1, also known as lipocortin-1 or p35, was originally discovered as a Ca2+-dependent substrate of the EGF receptor tyrosine kinase. It is a member of the annexin family of proteins that binds Ca2+ and phospholipids (3). Glucocorticoids exert their anti-inflammatory effect at least in part due to induction of ANAX1, which binds to membrane phospholipids through a calcium-dependent manner, resulting in inhibition of PLA2 and eicosanoid synthesis, including proinflammatory lipid mediators such as prostaglandins (4). Recent studies have indicated that the anti-inflammatory actions of ANAX1 are reproduced by Ac2-26 in many inflammatory and cellular settings (5,6). This peptide, as well as the whole protein, exerts its effects through activation of the formyl peptide receptor type 1 (FPR1) and type 2 (FPR2) (7). Ac2-26 has been shown to be beneficial in experimental models of organ injury, including inhibition of lung fibrosis (8) and brain injury (9).

In rat kidney, ANAX1 is expressed in the epithelia of Bowman’s capsule, the macula densa, medullary/papillary collecting ducts, and thick ascending limb, and its expression in distal tubular epithelial cells, including macula densa, collecting ducts, and thick ascending limb, increases in response to acute ischemic injury (10). Surprisingly, ANAX1 expression is not detectable in proximal tubule. This may be explained by expression differences between rats and mice, or ANAX1 is upregulated in diabetes. ANAX1 is also expressed in immune cells, particularly in macrophages and neutrophils (5,6,11). Of note, in the brain, ANAX1 is expressed only in microglia, the immune cell of the central nervous system, where it is expressed at high levels (12). ANAX1 has been shown to have anti-inflammatory and proresolving actions via regulation of macrophage polarization and efferocytosis. ANAX1 and Ac2-26 have been reported to inhibit cell proliferation and induce phagocytosis of apoptotic neutrophils by macrophages (13). Therefore, ANAX1 mimetics hold great potential as a therapeutic target for many inflammatory conditions, including DN, as indicated in the current study. In future studies, selective deletion of ANAX1 in distal epithelial cells is needed to confirm its role in the segment. In addition, the selective deletion of ANAX1 in immune cells may provide further insights into its role in protection against the development of DN.