Paracrine Mechanisms in Glycolytic Dysfunction of the Distal Tubule: A Novel Cause of Proximal Tubulopathy

• Applicant: Dr. Vera Anna Kulow
• Subject Area: Anatomy and Physiology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575886499

The enzyme 2,3-bisphosphoglycerate mutase (BPGM), previously considered erythrocyte-specific and known for its role in oxygen release via 2,3-BPG, has now been shown to exert a previously unknown function in the kidney. Analyses revealed both constitutive and stress-induced expression of BPGM in various murine and human models of acute and chronic kidney injury, including diabetic nephropathy and renal cell carcinoma. A nephron-specific, inducible Bpgm knockout mouse model (Bpgm-KO) revealed that the loss of BPGM in the distal tubule unexpectedly triggers early injury in the proximal tubule (PT), accompanied by dedifferentiation, metabolic reprogramming, inflammation, and the onset of fibrosis. Proteomic and computational analyses, supported by in vitro data, demonstrate that BPGM functions as a negative regulator of glycolysis. Its loss results in increased glucose uptake, enhanced lactate production, and accumulation of advanced glycation end products (AGEs) in distal tubules, located in close spatial proximity to damaged PT segments. In parallel, increased expression of the AGE receptor RAGE and activation of inflammatory pathways, including NF-κB expression in immune and epithelial cells, were observed. These findings suggest a previously undescribed paracrine signaling axis from the distal to the proximal nephron—an aspect of intrarenal communication that has so far received little attention. The aim of the planned research stay with Prof. Dr. Ina M. Schiessl (Aarhus University) is to investigate the molecular and cellular mechanisms underlying this distal-to-proximal signaling within the nephron. The focus lies on the role of BPGM and glycolytic activity in shaping tubular resilience under stress conditions. This will be addressed using serial intravital two-photon microscopy, functional tests in an AKI model, and in-depth molecular analyses. The goal is to identify a novel and pathophysiologically relevant mechanism in the renal tubular system. The specific scientific objectives are divided into two main work packages: 1. Deciphering dynamic mechanisms of distal-to-proximal paracrine communication in tubular injury (Work Package I – Elucidation of the kinetics of Bpgm-KO-mediated injury using two-photon microscopy). 2. Investigation of resilience and stress response of Bpgm-deficient nephrons in acute kidney injury (AKI) (Work Package II – Functional analysis of Bpgm-KO in the ischemia-induced acute kidney injury model).

• DFG Programme: WBP Fellowship
• International Connection: Denmark
• Host: Professorin Dr. Ina Maria Schießl, Ph.D.