2,3-Bisphosphoglycerate mutase, an innate renoprotective factor

• Applicants: Professor Dr. Michael Fähling; Professor Dr. Christian Rosenberger
• Subject Area: Anatomy and Physiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538820275

2,3-Bisphosphoglycerate adjusts hemoglobin’s affinity to oxygen and, thus, is thought to be solely useful for erythrocytes. We demonstrate that 2,3-Bisphosphoglycerat mutase (BPGM), which synthesizes 2,3-BPG in a glycolytic shunt reaction, is constitutively expressed in the kidney and pivotal for kidney integrity and adaptation to injury. Kidney BPGM is constitutively expressed in the distal portions of the nephron, most abundantly in distal convoluted tubules, and is upregulated in vitro by the tonicity-dependent transcription factor NFAT5, hyperosmolarity and hypoxia, as well as in vivo by acute kidney injury and diabetes. We demonstrate in vitro that BPGM inhibits glycolysis, potentially redirecting substrates towards the polyol and pentose phosphate pathways - the latter being crucial for radical scavenging. Remarkably, within 4 days, a doxycyclin-inducible, tubular specific Bpgm knockout in mice causes remote injury to proximal tubules as demonstrated by histology, e.g. the loss of brush border, and elevation of kidney injury markers KIM-1 and NGAL. Within the kidney convolute, proximal and distal nephron portions lie side by side or within short distance, thus allowing for exchange of signals. Bpgm knockout leads to increased advanced glycation end products (AGEs) in distal tubules, thus, AGEs and their receptors are prime candidates for the cross talk between tubular segments. However, injury resulting from Bpgm knockout is no longer detectable by day 16, but the kidney transcriptome is profoundly altered. Conceivably, such transcriptomic remodeling may render kidneys either more resistant or more susceptible to subsequent acute kidney injury (AKI). In most forms of AKI, tubular injury occurs in proximal tubules or in thick ascending limbs, but not in distal convoluted tubules. We propose that BPGM confers resistance to osmotic and hypoxic stress, produced by stress resistant cells in the distal nephron to the benefit of remote, more vulnerable parts of the proximal nephron. Considering all of our in vitro findings, we hypothesize that BPGM plays a crucial role in diabetic nephropathy, which represents a major risk factor for kidney injury. We propose that targeting the NFAT5-BPGM axis by physiologic and pharmacologic stimuli, might be a promising tool to prevent renal damage in diabetes. Within the present application, we pursue three topics: 1) Spatial and temporal characterization of kidney Bpgm knockout using single cell sequencing to provide insights to kidney injury and recovery; 2) Impact of kidney Bpgm knockout on subsequent AKI episodes and experimental diabetes; 3) Modulation of the NFAT5-BPGM axis by loop diuretics, thiazides and mineralocorticoid receptor antagonists to prevent kidney injury in diabetic nephropathy. Together, this project aims to translate our previous findings on cellular BPGM function into strategies to prevent renal injury in clinically highly relevant kidney diseases.

• DFG Programme: Research Grants