Biology subjects

Wenger, R. H.

Publications and source records attributed to Wenger, R. H..

3 recordsLinked to original sources

bioRxiv2026

Keto-gluconeogenic metabolic axis mirrors renal homeostasis and post-injury response in spatial transcriptomics

Metabolic disturbance is a key feature in acute kidney injury (AKI) and chronic kidney disease (CKD). The kidney highly depends on fatty acid metabolism; how renal cells rewire metabolism upon AKI and CKD transition remained unclear. Here, we combine spatial transcriptomics with biochemical analyses to characterize metabolic changes and intercellular interactions during AKI to CKD transition. Using aristolochic acid model of CKD, we spatio-temporally correlated changes in structure and function with metabolic profile during AKI to CKD transition. Surprisingly, keto-gluconeogenic metabolic axis was highly enriched in healthy kidney and paralleled injury phase transitions. Intercellular interaction analysis associated a subtype of macrophage with the drift to chronicity. Online scRNAseq datasets analysis confirmed altered keto-gluconeogenic metabolic pathways in ischemia-reperfusion injured mouse kidneys and AKI and CKD human kidney biopsies compared to healthy controls. This study identifies a metabolic axis transcriptionally mirroring renal homeostasis and injury responses, and tubulo-interstitial interactions that can be targeted to mitigate AKI to CKD transition.

pathology↗

bioRxiv2025

Tissular glucocorticoid reactivating enzyme 11beta-HSD1 drives pathogenic myofibroblast differentiation in chronic kidney disease

Chronic kidney disease (CKD) is a growing public health crisis, affecting over 10% of the global population and significantly increasing mortality and morbidity. Irrespective of its underlying cause, tubulointerstitial fibrosis (TIF) is a hallmark of CKD progression, with myofibroblasts being the primary effectors of renal fibrosis. Here, we show that 11beta-hydroxysteroid dehydrogenase type 1 (11{beta}-HSD1) is a critical driver of pathogenic myofibroblast differentiation and fibrosis in CKD. Using genetic deletion and pharmacological inhibition of 11{beta}-HSD1 in mouse models, we demonstrate a marked reduction in TIF severity and improved renal function, linked to the suppression of a regulatory myofibroblast (Reg-MF) subpopulation. Single-cell and spatial transcriptomics data reveal that 11{beta}-HSD1 is essential for the activation and expansion of Reg-MFs, which is conserved across species and predicts worse outcomes in CKD patients and kidney allograft recipients. These findings establish a direct link between 11{beta}-HSD1 activity and renal fibrogenesis, highlighting its role during the transition from pericytes to pathogenic Reg-MFs. Our results support 11{beta}-HSD1 inhibition as a promising therapeutic strategy to mitigate CKD progression, offering both mechanistic insights and translational potential for improving patient outcomes.

physiology↗

bioRxiv2021

Androglobin, a chimeric mammalian globin, is required for male fertility

Spermatogenesis is a highly specialised process, involving multiple dedicated pathways and regulatory check-points. Defects ultimately lead to male sub-fertility or sterility, and numerous aspects of mammalian sperm formation remain unknown. The predominant expression of the latest globin family member, androglobin (Adgb) in mammalian testis tissue prompted us to assess its physiological function in spermatogenesis. Adgb knockout mice display male infertility, reduced testis weight, impaired maturation of elongating spermatids, abnormal sperm shape and ultrastructural defects in microtubule and mitochondrial organisation. Epididymal sperm from Adgb knockout animals display multiple flagellar malformations including coiled, bifide or shortened flagella, and erratic acrosomal development. Following immunoprecipitation and mass spectrometry, we could identify septin 10 (Sept10) as interactor of Adgb. The Sept10-Adgb interaction was confirmed both in vivo using testis lysates, and in vitro by reciprocal co-immunoprecipitation experiments. Furthermore, absence of Adgb leads to mislocalisation of Sept10 in sperm, indicating defective manchette and sperm annulus formation. Finally, in vitro data suggest that Adgb contributes to Sept10 proteolysis in a calmodulin (CaM)-dependent manner. Collectively, our results provide evidence that Adgb is essential for murine spermatogenesis and further suggest that interdependence between Adgb and Sept10 is required for sperm head shaping via the manchette and proper flagellum formation.

developmental biology↗