The apoM/S1P Complex—A Mediator in Kidney Biology and Disease?

Abstract

Kidney disease affects more than 10% of the population, can be both acute and chronic, and is linked to other diseases such as cardiovascular disease, diabetes, and sepsis. Despite the detrimental consequences for patients, no good treatment options directly targeting the kidney are available. Thus, a better understanding of the pathology and new treatment modalities are required. Accumulating evidence suggests that the apolipoprotein M/sphingosine−1-phosphate (apoM/S1P) axis is a likely drug target, but significant gaps in our knowledge remain. In this review, we present what has so far been elucidated about the role of apoM in normal kidney biology and describe how changes in the apoM/S1P axis are thought to affect the development of kidney disease. ApoM is primarily produced in the liver and kidneys. From the liver, apoM is secreted into circulation, where it is attached to lipoproteins (primarily HDL). Importantly, apoM is a carrier of the bioactive lipid S1P. S1P acts by binding to five different receptors. Together, apoM/S1P plays a role in several biological mechanisms, such as inflammation, endothelial cell permeability, and lipid turnover. In the kidney, apoM is primarily expressed in the proximal tubular cells. S1P can be produced locally in the kidney, and several of the five S1P receptors are present in the kidney. The functional role of kidney-derived apoM as well as plasma-derived apoM is far from elucidated and will be discussed based on both experimental and clinical studies. In summary, the current studies provide evidence that support a role for the apoM/S1P axis in kidney disease; however, additional pre-clinical and clinical studies are needed to reveal the mechanisms and target potential in the treatment of patients.

Hepatic FoxOs link insulin signaling with plasma lipoprotein metabolism through an apolipoprotein M/sphingosine-1-phosphate pathway

“…Our human and mouse data suggest the possibility that the endothelial and lymphopoietic defects observed in the total-body Apom –/– mice may not occur in response to a partial reduction of HDL-S1P in humans or mice. Emerging evidence points to potentially important roles of HDL-ApoM-S1P in heart failure and kidney disease ( 61 , 68 ), and it will be of interest to examine whether this complex links insulin action to those pathologies. Further studies on the effects of ApoM-S1P will be of great relevance to understanding this evolutionarily conserved complex and its effects on insulin resistance and its vascular complications.…”

The known unknowns of apolipoprotein glycosylation in health and disease

“…ApoM is suggested to modulate HDL metabolism and exhibit anti-atherosclerotic functions. HDL-ApoM-S1P complex activates signaling cascades that maintain vascular integrity and decrease inflammatory reactions ( Christoffersen et al., 2011 ) and recent reports have described the role of ApoM in triglyceride turnover and renal diseases ( Bisgaard and Christoffersen, 2021 ). ApoM has one N- glycosylation site at Asn-135.…”

The Roles of Fatty Acids and Apolipoproteins in the Kidneys

“…ApoM is a small apolipoprotein of 26 kDa, which is highly produced in the liver and kidneys [ 198 , 199 ]; 95% of plasma apoM is associated with HDL, and 5% of plasma apoM is present in LDL, VLDL and chylomicron particles in humans and other animals [ 200 ]. ApoM has been reported to bind megalin and to be strongly expressed in kidney proximal tubular cells [ 201 ].…”

“…However, Brinck et al reported elevated S1P and diminished apoM in HDL particles in patients with CKD [ 205 ]. Uremia increases plasma apoM by 25% but has no effect on S1P [ 198 ]. Svarrer et al reported that urinary apoM serves as a biomarker of acute kidney injury in young children after heart surgery [ 206 ].…”

“…Svarrer et al reported that urinary apoM serves as a biomarker of acute kidney injury in young children after heart surgery [ 206 ]. Plasma apoM is also associated with apoA-I-containing HDL and plays a key role in the biology of plasma HDL [ 198 ].…”