WCN26-7585 HAEMOGLOBIN ELEVATION WITH SGLT2 INHIBITION IS MORE PRONOUNCED IN YOUNGER OBESE MEN WITH CHRONIC KIDNEY DISEASE

Introduction: Polycystic kidney disease (PKD) is a hereditary disorder that causes cysts to form in various organs, primarily the kidneys.PKD is classified as either autosomal dominant (AD) or autosomal recessive (AR).The levels of kynurenine, kynurenic acid, xanthurenic acid, and quinolinic acid-which are metabolic products of tryptophan in the kynurenine pathway-were significantly higher in the kidneys of Pkd1-RC/RC mice, which carry a mutation in the Pkd1 gene responsible for ADPKD, than in normal kidneys.However, the levels of tryptophan metabolites in the kidney of ARPKD are unknown.Therefore, we analyzed tryptophan metabolites in the kidneys of PCK rats harboring a mutation in the Pkhd1 gene, which is responsible for ARPKD.Methods: Blood and kidneys were collected from four-and 20-weekold PCK rats, as well as from age-matched SD rats that were used as normal controls.The blood was used to measure serum urea nitrogen (SUN), an indicator of renal function.The upper half of the left kidney was stained with hematoxylin and eosin (HE) staining, and the lower half was used for RNA extraction.The right kidney was frozen in liquid nitrogen, ground into powder, and analyzed for tryptophan metabolites using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS).Tryptophan metabolite levels were quantified using liquid chromatography-mass spectrometry (LC-MS).The gene expression levels of indoleamine 2,3-dioxygenase (Ido) 1 and Ido2 were detected using real-time PCR.Results: The kidney-to-body weight ratio, an indicator of PKD pathology, was significantly higher in 4-and 20-week-old PCK rats than in normal rats.SUN was only significantly increased in 20-week-old PCK rats.CE-TOFMS results showed that the levels of kynurenine, kynurenic acid, xanthurenic acid, and quinolinic acid were significantly increased in the kidneys of 20-week-old PCK rats compared to normal rats.Quantitative results for tryptophan metabolites in the kynurenine pathway showed no significant differences in levels between the kidneys of 4-week-old PCK and normal rats.However, levels of kynurenine, kynurenic acid, xanthurenic acid, and quinolinic acid were significantly higher in the kidneys of 20-week-old PCK rats.This is consistent with CE-TOFMS results.The expression level of Ido1, the enzyme responsible for the first step of tryptophan metabolism in the kynurenine pathway, did not differ in 20-week-old PCK rats compared to normal rats.However, the expression level of Ido2 was significantly increased.Conclusion: Similar to the kidneys of Pkd1-RC/RC mice, the kidneys of PCK rats exhibited significantly increased levels of kynurenine, kynurenic acid, xanthurenic acid, and quinolinic acid, which are tryptophan metabolites in the kynurenine pathway.This increase in metabolites is common in polycystic kidney.However, in four-weekold PCK rats, these metabolites in the kidney showed no difference compared to the kidney in normal rats.This suggests that these metabolites may play a role in the progression rather than its onset of PKD.Unlike the kidneys of Pkd1-RC/RC mice, only Ido2 expression was increased in the kidneys of PCK rats.This finding suggests that the mechanisms causing the increase in tryptophan metabolites in the kidneys differ between ADPKD and ARPKD.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.