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Dysregulation of the 3β-Hydroxysteroid Dehydrogenase Type 2 Enzyme and Steroid Hormone Biosynthesis in Chronic Kidney Disease

ABSTRACT:

Chronic kidney disease (CKD) presents a critical global health challenge, marked by the progressive decline of renal function. This study explores the role of the 3β-hydroxysteroid dehydrogenase type 2 enzyme (HSD3B2) and steroid hormone biosynthesis pathway in CKD pathogenesis and progression. Using an adenine-induced CKD mouse model, we conducted an untargeted metabolomic analysis of plasma samples to identify key metabolite alterations associated with CKD. Metabolic characteristics revealed significant metabolic shifts in CKD, with 61 metabolites increased and 65 metabolites decreased, highlighting the disruption in steroid hormone biosynthesis pathways influenced by HSD3B2. A detailed examination of seven key metabolites underscored the enzyme's central role. Further supported by Nephroseq and Human Protein Atlas data, HSD3B2 exhibited a strong correlation with kidney function. A drastic reduction in its expression in CKD-affected kidneys was confirmed through immunohistochemistry, Western blotting and qPCR analyses in both human and mouse tissues. Suppressed proliferation and increased apoptosis rate in HSD3B2 knocked down HK2 cells further demonstrated its significance in regulating renal pathophysiology. These findings underscore the potential of HSD3B2 as a clinical diagnostic and therapeutic target in CKD. While further studies are warranted to elucidate the mechanisms fully, our results provide valuable insights into the intricate interplay between steroid hormone biosynthesis and CKD, offering a promising avenue for precision medicine approaches and personalized treatment strategies.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS10715 | MetaboLights | 2024-10-10

REPOSITORIES: MetaboLights

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Project description:Renal gluconeogenesis accounts for half of systemic gluconeogenesis during starvation, but its regulatory mechanisms and implications in chronic kidney disease (CKD) remain unknown. In this study, using single-cell RNA sequencing of starved kidneys and various animal models, we aimed to identify key pathways involved in renal gluconeogenesis and their role in the development of hypoglycemia during starvation in diseased kidneys. Under the starvation condition, renal gluconeogenesis was highly induced in proximal tubule cells with FOXO1 activation. In renal tubular epithelial cells, starvation-induced FOXO1 activation was required to stimulate gluconeogenesis and promote glucose production. We further analyzed whether renal FOXO1-mediated gluconeogenesis is impaired in CKD. In CKD animal models, the kidneys exhibited reduced FOXO1 and gluconeogenic protein expression; however, serum glucose levels remained unchanged, suggesting that diminished renal gluconeogenesis does not significantly impact circulating glucose levels. When CKD mice were subjected to starvation, serum glucose levels were significantly reduced after 72 hours. In the CKD model, FOXO1 activation failed, accompanied by a lower induction of gluconeogenic protein expression. Similar to diseased condition, aged mice exposed to starvation also showed impaired gluconeogenic response in the kidney, contributing to reduced circulating glucose levels. Under the in vitro condition, we found that profibrotic TGFβ1 inhibits starvation-induced gluconeogenesis by directly suppressing the FOXO1 signaling pathway in tubular cells. Finally, we generated tubule-specific FOXO1 knockout (KO) mice by crossing FOXO1 floxed mice with Ksp-cre mice. These tubule-specific FOXO1 KO mice exhibited reduced expression of gluconeogenic genes in the kidney, leading to hypoglycemia during starvation. Collectively, we demonstrated crucial role of renal FOXO1 in gluconeogenesis during starvation, and its implication in kidney disease.

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Dysregulation of the 3β-Hydroxysteroid Dehydrogenase Type 2 Enzyme and Steroid Hormone Biosynthesis in Chronic Kidney Disease

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