Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury

Abstract

Sphingosine 1-phosphate analogs have a multitude of effects with the best characterized one being mediated through sphingosine 1-phosphate type 1 receptors (S1P1 receptor). Currently, S1P1 receptor agonists are being developed and tested for human disease. Because of the potent effect of S1P1 agonists to modulate the immune system, these compounds are ideal for blocking immune mechanisms that mediate acute kidney injury (AKI). This disorder continues to remain an important disease that is characterized by high morbidity and mortality. Currently there are no FDA approved drugs for the treatment of AKI. This review summarizes current knowledge on the mechanism of AKI due to ischemia-reperfusion and early studies that target S1P1 receptors for the treatment and prevention of AKI.Acute kidney injury (AKI) is a burgeoning medical disease. Based upon the National Health Statistics and National Hospital Discharge Survey, between 1979 and 2002 there has been an increase in hospitalization for AKI (ICD9 = 584.0 through 584.9) from 35,000 to 650,000 cases per year (P. Eggers, Am Soc. Nephrol., 2004). Overall mortality has been reported to be 40-60% in critically ill patients [1][2][3]. The estimated annual health care expenditures attributed to hospital-acquired AKI exceed $10 billion [4]. Furthermore there is recognition that there is an increase in the end stage renal disease (ESRD) population due to AKI. In patients suffering from AKI, 13.4% of patients (or 30% of patients with AKI superimposed on chronic kidney disease) will progress to ESRD in 3 years (P. Eggers, Am Soc. Nephrol, 2004). Thus to overcome barriers to successful treatment of AKI, well designed clinical trials will need to be based on a precise understanding of the molecular, cellular and immunological basis of AKI [5]. Novel pharmacological agents need to be tested in preclinical and clinical trials. This review focuses on the pathogenesis of ischemia-reperfusion and one class of agents, agonists of sphingosine 1-phosphate receptors, that are potential agents in the treatment of AKI. Pathogenesis of acute kidney ischemia reperfusion injuryAKI from ischemia is initiated by unfavorable changes in renal blood flow as a consequence of vasospasm, alterations in ultrafiltration coefficient, tubular obstruction and/or back-leak. The renal medulla is particularly susceptible to renal ischemia because of a low oxygen tension (PO 2 of 10-20 mmHg) [6]. With loss of blood flow, oxygen content is reduced even farther due to red blood cell and leukocyte trapping and a decrease in medullary blood flow. Hypoxic injury or reperfusion injury results in endothelial cell dysfunction that alters the balance of vascular tone of vasoactive agents such as endothelin and nitric oxide [7,8,[9][10][11]. In addition Dendritic cell activation of NKT cells and IFN-γ in kidney IRITissue resident macrophages and dendritic cells originate from a heterogeneous population of bone marrow-derived monocytes [23][24][25][26] Sphingosine 1-phosphate (S1P) receptors and analogsSphing...

Sphingosine-1-phosphate acts as a key molecule in the direct mediation of renal fibrosis

“…). These findings suggest that FTY720 has beneficial effects and is able to reduce the progression of the disease toward chronic tubulointerstitial fibrosis and renal insufficiency through its ability to deplete lymphocytes and stop the inflammatory reactions (Okusa and Lynch ; Peters et al. ).…”

“…Taken together, the in vitro and in vivo findings of the effects of fibrosis suggested that S1P is involved in fibrosis. Renal fibrosis has been shown to occur through inflammatory pathways involving S1PR1 (Okusa and Lynch 2007 ). In this study, the direct effects of S1P on renal fibrosis and not those mediated by inflammation were examined in a nude mouse.…”

“…FTY720 has been shown to be effectively protective against experimental IRI (Awad et al 2006 ). Furthermore, it has been clarified that the primary tissue protective role of S1P is mediated by the S1PR1 (Awad et al 2006 ; Okusa and Lynch 2007 ), resulting in a decrease in immune‐mediated cells and inflammatory cells in the lesions of the kidney. In addition, the role of S1P in a chronic model of kidney disease has been explored in a rat model of anti‐Thy1‐induced chronic progressive glomerulosclerosis (Peters et al 2004 ).…”

Cellular and Molecular Mechanisms of AKI

“…Examples of receptors involved in AKI-mediated injury include the FAS receptor and TGFb receptor. 40,41 Examples of receptors involved in epithelial cytoprotection and repair include the EGF receptor, 42 HGF receptor (c-Met), 43 sphingosine-1-phosphate receptor, 44 and netrin-1 receptor. 45 Many questions relating to the role of receptors in AKI remain unanswered, including the sources of the putative ligands, mechanisms of receptor activation, and signaling pathways involved in protection from injury or involved with epithelial repair.…”

Hemo-Vasculogenesis in the Kidney and Heart

“…Both AKI and CKD, especially at the end--stages, have shown an alarming increase for the past 30 years in the US and worldwide. 62,63 Many kidney diseases have primary or secondary vascular lesions, which can be accelerated by risk factors, such as hypertension, diabetes and obesity. 63 Generation of new vessels in the kidney is not confined to embryonic development but is also a mechanism activated in response to disease.…”