2,3-Bisphosphoglycerate mutase (BPGM) and kidney—Potential new role in the coordination of metabolic needs of renal epithelia

Abstract

In a recent issue of Acta Physiologica, Kulow et al. (2025) propose that the enzyme 2,3-Bisphosphoglycerate mutase (BPGM) is involved in the pathophysiology of acute kidney injury. BPGM is well known for the production of 2,3-Bisphsophoglycerate (2,3-BPG) in erythrocytes, where 2,3-BPG exerts crucial modulation of the affinity by which hemoglobin binds oxygen and hence shifts the O₂ equilibrium curve to the right. Kulow et al. (2025) now reveal that this legendary enzyme is expressed in the distal parts of the nephron in the kidney.¹

Recent advances in proteomics and transcriptomics enable to establish correlations of gene or protein expression of a huge variety of products, and oftentimes identify products that would not have been in focus with more traditional approaches. Correlations, however, do not establish causality, and finding a physiological “home” of these newly found products often involves dedicated and laborious efforts; This is exactly what Kulow et al. (2025) do in their recent study in Acta Physiologica.

In 2013, the same research group at Charite showed that BPGM is upregulated acute kidney injury in mice² and Kulow et al.¹ therefore developed an inducible kidney-specific knockout mouse model to understand the physiological ramifications of this surprising finding. These mice consistently developed signs of acute injury within days after knock-out induction. So, now there is information about increased expression of BGPM during disease and evident disease development in case of lack of expression. The latter indicates a bona fide physiological function of BGPM, which goes missing after knockout.

Most of the known functions of BGPM and 2,3-BGP production stem from mammalian erythrocytes. These nuclei- and mitochondria-free hemoglobin/O₂ transporters rely on anaerobic glycolysis for their entire metabolic needs. In a sideline—but regulatory—metabolic pathway, BGPM produces 2,3-BGP during the process of glucose metabolism. As recently reviewed in Acta Physiologica, the understanding of erythrocyte metabolism also got a substantial boost by new “-omics” findings in the recent years.³ BGPM expression and 2,3-BGP production have also been described beyond erythrocytes, such as placenta⁴ and astrocytes.⁵ The placental expression is perhaps the easiest to understand in analogy as also here O₂ release between compartments has to be regulated. In the case of erythrocytes, the unloading of oxygen to the needy tissues (Figure 1), in this case of the placenta the transfer of oxygen from maternal to fetal hemoglobin. There are of course no direct oxygen-hemoglobin interactions in astrocytes, but their metabolism subserves neuronal cells. In analogy to these examples, one can speculate that BPGM expression serves in specialized sensor cells to change metabolism to support maintenance in profiter-cells or tissues. Besides the supply of energy, the pathophysiological interesting clearance of radicals might also be important in this intercellular interchange/support.

Interestingly, BPGM is expressed in the distal nephron of the kidney, but the proximal tubuli are damaged in response to knockdown of BPGM. So, Kulow et al. propose a distal-to-proximal crosstalk phenomenon. From the perspective of renal transport physiology—and not necessarily in terms of pathophysiology—this is a very interesting concept. Besides renal epithelial transport, renal cell metabolism and energy demand also vary among the various segments. Proximal tubule transport shows highly effective mass transport of water, electrolytes, and energy substrates coupling trans- and paracellular transport mechanisms. The proximal tubular epithelium is thereby facing the task of complete reabsorption of the freely filtered glucose, very effectively using sodium-coupled glucose transport. Besides glucose transport, it is able to perform gluconeogenesis. It therefore serves systemic glucose homeostasis, but usually does not metabolize glucose itself.⁶ This can be also seen and investigated under experimental in vitro conditions: Isolated perfused proximal tubules can usually be observed for over an hour. However, if the experimental solution only contains glucose as an energy supply (no ketone bodies or fatty acids) the proximal tubule dies within 10 min after the start of the experiment, showing similar damage and cast formation as in acute kidney injury histology,⁷ own observations. This emphasizes that the proximal tubule can not be the primary site for BPGM expression (under normal conditions no glycolysis), but might be the segment most in need of metabolic support. In the case of chronic disease, the highly complex proximal tubular metabolism can adapt.⁸ The thin limbs live in a challenging environment and have very few mitochondria. They rely therefore to an extent on anaerobic energy metabolism or no energy consumption at all, that is, on passive transport facilitated by the counter-current mechanism.⁹ The thick ascending limb and distal convoluted tubule have very high NKA activity as their transport properties are fueled by secondary active transport processes. The collecting duct is a segment that can change its transport properties considerably, depending on hormones, and therefore has also changing energy requirements. The distal nephron segments, in contrast to the proximal tubule, can use glucose as an energy source. The basolateral compartment of the kidney is also unique as it is the site of high solute/molecule fluxes and has specialized fibroblasts embedded. Some of them are again strongly linked to O₂ homeostasis as they sense hypoxia and produce erythropoietin.¹⁰

From the perspective of renal architecture and cortical histological configuration (Figure 1), the idea of BPGM being expressed in one cell, but influencing neighboring cells under physiological and pathophysiological conditions in a paracrine fashion is an intriguing concept. Future detailed investigations will further clarify the basolateral flow of substances or signals.

Nina Himmerkus and Tobias Wang drafted, wrote and edited the manuscript.

Tobias Wang is supported by Novo Nordisk Fonden, Grant/Award Number: NNF21OC0071589.