Sphingosine 1-phosphate signaling in perivascular cells enhances inflammation and fibrosis in the kidney

Abstract

Chronic kidney disease (CKD), characterized by sustained inflammation and progressive fibrosis, is highly prevalent and can eventually progress to end-stage kidney disease. However, current treatments to slow CKD progression are limited. Sphingosine 1-phosphate (S1P), a product of sphingolipid catabolism, is a pleiotropic mediator involved in many cellular functions, and drugs targeting S1P signaling have previously been studied particularly for autoimmune diseases. The primary mechanism of most of these drugs is functional antagonism of S1P receptor-1 (S1P1) expressed on lymphocytes and the resultant immunosuppressive effect. Here, we documented the role of local S1P signaling in perivascular cells in the progression of kidney fibrosis using primary kidney perivascular cells and several conditional mouse models. S1P was predominantly produced by sphingosine kinase 2 in kidney perivascular cells and exported via spinster homolog 2 (Spns2). It bound to S1P1 expressed in perivascular cells to enhance production of proinflammatory cytokines/chemokines upon injury, leading to immune cell infiltration and subsequent fibrosis. A small-molecule Spns2 inhibitor blocked S1P transport, resulting in suppression of inflammatory signaling in human and mouse kidney perivascular cells in vitro and amelioration of kidney fibrosis in mice. Our study provides insight into the regulation of inflammation and fibrosis by S1P and demonstrates the potential of Spns2 inhibition as a treatment for CKD and potentially other inflammatory and fibrotic diseases that avoids the adverse events associated with systemic modulation of S1P receptors.

2-Aminobenzoxazole Derivatives as Potent Inhibitors of the Sphingosine-1-Phosphate Transporter Spinster Homolog 2 (Spns2)

“…Recently, we participated in a study that demonstrated Spns2 deficiency in kidney perivascular cells, but not tubular cells, ameliorates kidney fibrosis through modulation of inflammatory cells. This result was unexpected in that an S1P modulator (fingolimod) was ineffective in these models . Taken together, these reports indicate that Spns2 might be a useful drug target.…”

“…Because Spns2 plays a role in both lymphocyte trafficking and S1P-mediated inflammation, we hypothesize that blocking S1P transport could be another mechanism for manipulating the S1P pathway that circumvents the adverse effects of S1P modulators. Recent studies have shown that Spns2 is a potential therapeutic target for multiple sclerosis, and kidney fibrosis. , Unfortunately, small molecule inhibitors of Spns2 are lacking, which impedes the understanding of the physiological role of this transporter. In the current structure–activity relationship study, we interrogated three regions of a pharmacophore based on 16d (SLF1081851) .…”

“…Recent studies have shown that Spns2 is a potential therapeutic target for multiple sclerosis, 38 and kidney fibrosis. 39,40 Unfortunately, small molecule inhibitors of Spns2 are lacking, which impedes the understanding of the physiological role of this transporter. In the current structure−activity relationship study, we interrogated three regions of a pharmacophore based on 16d (SLF1081851).…”

“…The former phenotype is reported in all mice strains rendered deficient in Spns2, while the literature is unsettled regarding the later phenotype ( vide supra ). In addition, SLF1081851 ameliorated kidney fibrosis in both a folic acid toxicity and a surgical (ischemia reperfusion injury) model at 10 mg/kg . While SLF1081851 has proven to be an informative lead compound, its utility is limited by low potency and a narrow therapeutic window (maximum tolerable dose <20 mg/kg).…”

Editorial – Connective Tissue Growth Factor: A Key Factor Among Mediators of Tissue Fibrosis

“…[32] Immune cells, such as macrophages, mediate inflammatory responses that are integrated with other profibrotic processes. [29,31,[33][34][35] However, the details of these interactions remain poorly understood, but single-cell genomic, proteomic, and transcriptomic techniques are further unraveling the specific cell subtypes and their interactions in pathophysiology of fibrosis in various tissues.…”