title: Reduced Activity of Sphingosine-1-Phosphate Lyase Induces Podocyte-related Glomerular Proteinuria, Skin Irritation, and Platelet Activation.
abstract: Sphingosine-1-phosphate (S1P) lyase is considered as a drug target in autoimmune diseases based on the protective effect of reducing activity of the enzyme in animal models of inflammation. Since S1P lyase deficiency in mice causes a severe, lethal phenotype, it was of interest to investigate any pathological alterations associated with only partially reduced activity of S1P lyase as may be encountered upon pharmacological inhibition. Both genetic reduction of S1P lyase activity in mice and inhibition of S1P lyase with a low-molecular-weight compound in rats consistently resulted in podocyte-based kidney toxicity, which is the most severe finding. In addition, skin irritation and platelet activation were observed in both instances. The similarity of the findings in both the genetic model and the pharmacological study supports the value of analyzing inducible partially target-deficient mice for safety assessment. If the findings described in rodents translate to humans, target-related toxicity, particularly podocyte dysfunction, may limit chronic systemic treatment of autoimmune diseases with S1P lyase inhibitors. Furthermore, partial deficiency or inhibition of S1P lyase appears to provide an in vivo rodent model to enable studies on the mechanism of podocyte dysfunction.
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland jens.schuemann@novartis.com.
authors: Jens
authors: J
authors: Schümann
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Armelle
authors: A
authors: Grevot
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: David
authors: D
authors: Ledieu
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Armin
authors: A
authors: Wolf
authors: Autoimmunity, Transplantation, and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Anna
authors: A
authors: Schubart
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Alessandro
authors: A
authors: Piaia
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Esther
authors: E
authors: Sutter
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Serge
authors: S
authors: Côté
authors: Autoimmunity, Transplantation, and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Christian
authors: C
authors: Beerli
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: François
authors: F
authors: Pognan
authors: Autoimmunity, Transplantation, and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Andreas
authors: A
authors: Billich
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Pierre
authors: P
authors: Moulin
authors: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Ursula Junker
authors: UJ
authors: Walker
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D015539:Platelet Activation / Q000502:physiology*; D050199:Podocytes / Q000201:enzymology*; D011507:Proteinuria / Q000097:blood / Q000201:enzymology*; D051381:Rats; D012867:Skin / Q000201:enzymology / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D013629:Tamoxifen; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)
keywords: kidney; podocyte dysfunction.; sphingosine-1-phosphate lyase