Renal gluconeogenesis: a key metabolic hub in health and kidney disease

ABSTRACT

Gluconeogenesis, responsible for maintaining systemic glucose availability during fasting, has long been thought to be a process mainly performed by the liver. Over the past decades, physiological and molecular studies have established the kidney as a major site of endogenous glucose production. Renal gluconeogenesis occurs mainly in proximal tubular epithelial cells, where it integrates substrate utilization, hormonal signaling, and acid–base regulation to support systemic homeostasis. The kidney relies on distinct regulatory inputs and dynamically adapts gluconeogenic flux to nutritional state, metabolic acidosis, and interorgan metabolite exchange. As a highly metabolically active organ, it sustains the important energetic demands and differentiated state of proximal tubular cells through a high mitochondrial density. Renal gluconeogenesis is tightly coupled to ammoniagenesis and tricarboxylic acid cycle dynamics in addition to its contribution to glucose homeostasis, thus being a key determinant of mitochondrial integrity. Increasing evidence indicates that disruption of this metabolic program is a consistent feature of acute and chronic kidney disease, where suppression of gluconeogenesis accompanies epithelial dedifferentiation, mitochondrial dysfunction, and fibrotic remodeling. In this review, we synthesize current knowledge on the regulation and function of renal gluconeogenesis and discuss its emerging role as a central determinant of mitochondrial integrity, tubular resilience, and kidney disease progression.

INTRODUCTION

The kidney is increasingly recognized as a metabolically active organ. Indeed, proximal tubular epithelial cells (PTECs) have exceptionally high energy requirements [1–3] to support solute reabsorption, and to maintain electrolyte and fluid balance, blood pressure regulation, and acid–base homeostasis [4–6]. To sustain these energy-intensive functions, PTECs rely on tightly coordinated metabolic programs that preserve cell epithelial differentiation and continuous transport activity [7, 8]. Among these programs, renal gluconeogenesis has emerged as a central feature of proximal tubular (PT) metabolism.

Historically considered as a minor contributor relative to hepatic glucose production, the kidney is now recognized as a major source of endogenous glucose, particularly during fasting and metabolic stress [6, 7]. The gluconeogenic capacity of the kidney was first described in the early twentieth century [9] and subsequently documented in experimental models and in humans, including patients with kidney disease [10]. Importantly, renal gluconeogenesis is not an isolated glucose-producing pathway but is functionally coupled to mitochondrial oxidative metabolism, ammoniagenesis, and acid–base regulation [11, 12], positioning the PT as a central coordinator linking systemic glucose homeostasis, nitrogen handling, and mitochondrial energy production.

In this review, we summarize recent evidence supporting renal gluconeogenesis as a key component of PT metabolic integration at the intersection of tubular cell energy production and systemic metabolism. We discuss the molecular and mitochondrial mechanisms that regulate this process and highlight its broader implications for systemic metabolic health and kidney disease.

GLUCONEOGENESIS: FOCUS ON THE KIDNEY

Glucose is a central metabolic substrate whose plasma concentration is tightly regulated to ensure adequate supply to glucose-dependent tissues. Endogenous glucose production occurs through two complementary pathways: glycogenolysis and gluconeogenesis [13]. Glycogenolysis is a catabolic process that mobilizes stored glycogen to generate glucose-6-phosphate, which is hydrolyzed by glucose-6-phosphatase (G6PC) to release free glucose into the circulation. In contrast, gluconeogenesis is an anabolic pathway that generates glucose de novo from nonhexose precursors, predominantly lactate, glutamine, and glycerol in the postabsorptive state [14, 15] (Fig. 1A). This process involves 11 enzymatic reactions, 7 shared with glycolysis and 4 irreversible, rate-limiting steps catalyzed by pyruvate carboxylase (PC), cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), fructose-1,6-bisphosphatase (FBP1), and G6PC [13] (Fig. 1A). PC converts pyruvate into oxaloacetate (OAA), which PCK1 subsequently converts into phosphoenolpyruvate (PEP); FBP1 hydrolyzes fructose-1,6-bisphosphate (F1,6-BP) to fructose-6-phosphate, and G6PC produces free glucose for release into the circulation (Fig. 1A). These enzymes are spatially compartmentalized, with PC located in the mitochondrial matrix, PCK1 and FBP1 in the cytosol, and G6PC anchored in the endoplasmic reticulum membrane [16, 17].

Figure 1:

Gluconeogenesis is tightly coupled to ammoniagenesis and the TCA cycle in the kidney. (A) Gluconeogenesis pathway in PTECs. (B) Overview of ammoniagenesis pathway in PTECs showing renal glutamine metabolism with transporters B°AT1 and SNAT3 leading to ammonia generation and release in the urine. (C) TCA cycle in the mitochondrion, showing both gluconeogenesis and glycolysis pathways.

Renal contribution to systemic glucose homeostasis

Under physiological fasting conditions (≈14–16 h), an increasing proportion of circulating glucose is derived from gluconeogenesis, with the remainder supplied by hepatic glycogenolysis [17, 18]. Beyond the liver, the kidney is now recognized as a significant complementary contributor to endogenous glucose production. Under certain conditions, both the kidney and the intestine express the full gluconeogenic enzyme activity necessary to release glucose into the circulation [19, 20]. Because renal epithelial cells contain minimal glycogen, renal glucose output relies primarily on de novo glucose synthesis. This function is predominantly carried out by PTECs, particularly within the S3 segment, which express high levels of PCK1, FBP1 and G6PC [17]. In humans, the kidney contributes ∼20%–25% of endogenous glucose production in the postabsorptive state, rising to 40%–50% during prolonged fasting (>16–24 h) [13, 21, 22]. Thus, during sustained fasting or metabolic stress, the kidney becomes essential for maintaining systemic glucose availability.

Hormonal and metabolic regulation of renal gluconeogenesis

Physiological studies indicate that renal and hepatic gluconeogenesis are coordinated yet differentially regulated, a concept often referred to as hepatorenal reciprocity, whereby the kidney progressively increases its contribution to endogenous glucose production as hepatic glycogen stores decline [23]. Notably, renal gluconeogenic gene expression can be maintained or even induced, during prolonged fasting, whereas hepatic gluconeogenic programs may decline, highlighting organ-specific regulatory mechanisms [24]. While hepatic gluconeogenesis is classically controlled via transcriptional regulation of G6pc1 and Pck1 downstream of glucagon signaling, the upstream mechanisms governing renal gluconeogenesis remain incompletely understood [25, 26]. Renal gluconeogenesis is dynamically modulated by hormonal signals, including insulin and glucocorticoids, whereas the contribution of glucagon is less well defined [25, 27].

PTECs abundantly express insulin receptors, and under fed conditions, insulin suppresses renal gluconeogenesis through IRS/PI3K/AKT/FOXO1 signaling axis, thereby repressing key gluconeogenic enzymes, including PCK1 [28, 29]. In parallel, PT glucose reabsorption via sodium–glucose co-transporter 1 (SGLT1) and SGLT2 modulates the intracellular nicotinamide adenine dinucleotide (NAD+/NADH) ratio, promoting sirtuin 1 (SIRT1)-dependent repression of PCK1 and further constraining gluconeogenic flux [29].

During fasting, the decline in circulating insulin relieves this repression, allowing induction of renal gluconeogenesis. Elevated glucocorticoid levels further stimulate gluconeogenic gene expression in PTECs through glucocorticoid receptors signaling, contributing to the adaptive increase in renal glucose production during metabolic stress [17]. In contrast, glucagon receptor expression is highest in the thick ascending limb and distal nephron, with lower but detectable levels in PT [30], and its direct role in regulating renal gluconeogenesis remains uncertain [25, 27].

Renal gluconeogenesis is also strongly influenced by substrate availability and the metabolic context. Under postabsorptive conditions, lactate is the predominant gluconeogenic substrate, followed by glutamine and glycerol [6, 10]. This substrate preference reflects both systemic availability and the metabolic specialization of PTECs. Substrate utilization is further modulated by systemic acid–base status: metabolic acidosis is a potent stimulus, shifting glutamine to become the principal gluconeogenic precursor, functionally linking gluconeogenic flux to ammoniagenesis and bicarbonate generation. Through this mechanism, renal glucose production is directly linked to acid–base homeostasis [4, 13].

Metabolite-based signaling integrates renal gluconeogenesis into whole-body energy metabolism. During ketogenic states, liver-derived β-hydroxybutyrate has been reported to stimulate renal gluconeogenesis, enhancing renal gluconeogenic gene expression, including Pck1 and G6pc1, and promoting both glucose production and ammoniagenesis in PTECs [24]. Mechanistically, this response involves CCAAT/enhancer-binding protein beta (C/EBPβ)-dependent transcriptional activation, revealing a metabolite-driven axis linking hepatic ketone production to renal glucose metabolism and acid–base regulation. Early in fasting, this stimulatory effect predominates, whereas during prolonged starvation, increased renal ketone uptake and oxidation may progressively substitute on glutamine-derived energy, limiting excessive ammoniagenesis while preserving gluconeogenic capacity and acid–base balance [31].

Within this framework, renal gluconeogenesis also contributes to a lactate–glucose shuttle analogous to the hepatic Cori cycle [32]. Lactate derived from peripheral anaerobic glycolysis is taken up by the kidney and serves as a major carbon source for renal glucose production [6, 10]. Lactate handling is spatially organized along the nephron. In the PT, lactate is converted to pyruvate and directed toward mitochondrial oxidation or gluconeogenesis, supporting glucose release into the circulation, whereas in distal segments, lactate is primarily oxidized to meet local energy demands [33, 34].

Adipokine signaling provides an additional regulatory layer linking systemic energy status to renal substrate utilization. Endogenous renal adiponectin promotes gluconeogenesis by enhancing pyruvate and fatty acid utilization in PTECs, supporting mitochondrial oxidative metabolism and sustaining gluconeogenic flux [35].

Collectively, these findings indicate that renal gluconeogenesis is governed by an integrated network of hormonal cues, substrate availability, metabolite signaling, and interorgan as well as intrarenal metabolic coupling distinct from, yet complementary to, hepatic regulation.

Through this coordinated handling of substrates, the kidney contributes simultaneously to systemic glucose supply, lactate clearance, and acid–base regulation, particularly during fasting and acidotic states.

BEYOND GLUCOSE: FUNCTIONAL COUPLING OF RENAL GLUCONEOGENESIS WITH AMMONIAGENESIS AND TCA CYCLE INTEGRITY

Glutamine-dependent coupling of gluconeogenesis and ammoniagenesis

In the PTECs, gluconeogenesis is tightly coupled to ammoniagenesis, thereby linking renal glucose production to acid–base homeostasis [11]. Glutamine serves as the central substrate connecting these processes. Even under basal conditions, renal gluconeogenesis relies substantially on glutamine metabolism. Under acidotic conditions, PTECs increase glutamine uptake through the apical transporter B⁰AT1 (SLC6A19) and the basolateral transporter SNAT3 (SLC38A3), thereby enhancing intracellular substrate availability for both ammoniagenesis and gluconeogenesis [6, 36, 37] (Fig. 1B).

Within mitochondria, glutaminase 1 (GLS1) converts glutamine to glutamate, which is metabolized by glutamate dehydrogenase 1 to generate α-ketoglutarate (α-KG) and ammonium (NH₄⁺) [38] (Fig. 1B). Ammonium is excreted via NH₃ diffusion, luminal proton secretion mediated by the transporter sodium-hydrogen exchanger 3 (NHE3), forming NH₄⁺ in the lumen (Fig. 1B), along with transport by Rh-family proteins (Rhcg and Rhbg) further in the nephron [39]. Meanwhile, α-KG fuels the tricarboxylic acid (TCA) cycle, supporting gluconeogenic flux. Bicarbonate generated during glutamine metabolism is exported across the basolateral membrane via the sodium bicarbonate cotransporter 1 (NBC1), contributing to systemic pH buffering capacity [4, 39] (Fig. 1B).

Experimental evidence indicates that disruption of renal gluconeogenesis has direct consequences for systemic acid–base balance [40, 41]. PCK1, highly expressed in the kidney cortex as well as in the liver and intestine [42, 43], occupies a central position in this network. In mice with tubular-specific deletion of Pck1, renal gluconeogenesis is severely impaired; although systemic glucose and lactate levels are maintained through hepatic compensation, these animals develop marked metabolic acidosis consistent with proximal renal tubular acidosis and reduced proximal ammoniagenesis [43] (Table 1).

Table 1:

Impairment or restoration of gluconeogenic enzymes and the impact on kidney health and metabolism in humans and rodents.

Gluconeogenic enzyme	Physiological role in kidney	Species	Disease context/ experimental model	Renal/metabolic phenotype
Renal gluconeogenic gene program (PCK1, FBP1, G6PC, PC)	Renal Gluconeogenesis and couples metabolism to ammoniagenesis and acid–base balance	Human	CKD, AKI, DKD, ADPKD, and immune-mediated nephropathies	Coordinated repression of gluconeogenic genes associated with metabolic rewiring, tubular dedifferentiation, and fibrosis [51, 52, 54, 56, 60, 63, 64]
PCK1	Rate-limiting gluconeogenic enzyme, supports TCA cycle cataplerosis and mitochondrial energy metabolism	Mouse	Tubule-specific Pck1 deletion in AKI/CKD and diabetic nephropathy models	Impaired gluconeogenesis, mitochondrial dysfunction, metabolic acidosis, tubular injury, and fibrosis [43, 50, 52]
PCK1 restoration	Restores gluconeogenic flux and mitochondrial metabolic homeostasis	Mouse	Tubule-specific Pck1 knock-in in AKI/CKD models, kidney specific Pck1 knock-in in IgA nephropathy model, transgenic overexpression in DKD model	Preserves mitochondrial integrity and attenuates inflammatory and fibrotic signaling [43, 50, 52, 56]
PC	Anaplerotic conversion of pyruvate to OAA sustaining TCA cycle flux	Mouse	Proximal tubule-specific Pcx deletion	Mitochondrial damage, activation of SQOR–cGAS–STING signaling, glycolytic reprogramming, and interstitial fibrosis [59]
G6PC	Terminal step of gluconeogenesis enabling renal glucose release	Mouse	Kidney-specific G6pc deletion	Glucose-6-phosphate accumulation, mitochondrial dysfunction, oxidative stress, and progressive tubulointerstitial disease with cystic changes [19, 64]

This integrated metabolic architecture enables the kidney to simultaneously excrete acid and sustain glucose production. Therefore, renal gluconeogenesis should not be viewed solely as a glucose-producing pathway but as a core component of nitrogen handling and proton disposal, explaining its strong sensitivity to systemic pH.

Coupling of gluconeogenesis and cataplerotic control of TCA cycle dynamics

The kidney is among the most metabolically active organs, with an energetic expenditure approaching ≈400 kcal/kg tissue per day. It contains the second-highest mitochondrial density in the body, with oxygen consumption surpassed only by the heart [3, 44, 45]. These metabolic requirements are driven by the PT, which reabsorbs most filtered nutrients and electrolytes. PTECs rely on a high mitochondrial density to meet this high energy burden, generating ATP predominantly through aerobic respiration, supported by the relatively higher oxygen availability in the renal cortex compared with the medulla [46]. These cells use various substrates, including oxidized fatty acids, lactate, and glutamine to sustain ATP production. Importantly, this oxidative metabolism is highly adaptable, allowing the PT to shift its principal energy source in response to changes in substrate availability, hormonal cues, or injury-induced metabolic reprogramming [6, 47, 48]. Consequently, maintaining mitochondrial homeostasis is essential for PT function and for preserving global renal physiology.

Mitochondrial ATP production relies on continuous TCA cycle turnover, which requires a dynamic balance between anaplerosis (replenishment of TCA intermediates) and cataplerosis (their removal to support other metabolic pathways). These opposing processes are critical for sustaining oxidative metabolism. In the liver, PCK1-mediated cataplerosis provides a key link between gluconeogenesis and mitochondrial energy production by converting OAA to PEP [49].

Recent evidence demonstrates that PCK1 mediates a cataplerotic function in mouse PT [43, 50]. PCK1, which is highly expressed in this nephron segment, supports both gluconeogenesis and the maintenance of TCA cycle dynamics by converting OAA into PEP, thereby sustaining mitochondrial ATP production through cataplerosis. Indeed, deletion of Pck1 led to a clear alteration of mitochondrial flux in vivo, altering TCA function and resulting in alteration of mitochondria structure and function, and decreased ATP production in mice [43] (Table 1). In humans, reduced PCK1 expression in kidney biopsies correlates with markers of mitochondrial dysfunction, TCA accumulation and fibrosis severity, suggesting that impaired cataplerotic flux may also contribute to metabolic instability in human chronic kidney disease (CKD) [51, 52] (Table 1). These findings identify renal gluconeogenesis as a critical determinant of mitochondrial integrity and energy homeostasis in PTECs.

GLUCONEOGENESIS IN KIDNEY DISEASE

Failure of renal gluconeogenesis as a hallmark of tubular injury

Human data

In patients with kidney disease, metabolic gene profiling demonstrates profound tubular metabolic reprogramming, characterized by reduced oxidative capacity, decreased gluconeogenesis, and enhanced glycolysis [51, 53–55].

Analysis of human kidney biopsies across multiple nephropathies reveals that expression of PT gluconeogenic enzymes, including PCK1, is reduced and correlated with renal function, interstitial fibrosis, and estimated glomerular filtration rate (eGFR) decline [51, 56]. These correlations firmly establish suppression of gluconeogenesis as a feature of human kidney diseases [51, 56]. Integrative multi-omics analyses identify repression of gluconeogenic pathways as a hallmark of progressive CKD [57, 58]. The failed repair tubular phenotype, observed in human CKD biopsies, is characterized by persistent dedifferentiation, chromatin remodeling, and sustained metabolic reprogramming. In this context, PCK1 expression is selectively reduced in PTECs progressing toward unresolved repair states, as demonstrated in human datasets, together with depletion of gluconeogenic intermediates and a shift toward glycolytic metabolism, indicating functional loss of gluconeogenic capacity at the tissue level [58] (Table 1).

The upstream regulation of renal gluconeogenesis during injury appears to be closely coupled to epithelial identity programs. In the healthy kidney, transcription factors such as hepatic nuclear factor 4 α (HNF4α) help to maintain PTECs differentiation and coordinate metabolic gene expression, including pathways related to gluconeogenesis in human datasets [58]. During injury, failure to restore HNF4α activity coincides with persistent activation of injury-associated transcriptional programs, including SOX family factors, and parallels repression of PCK1 and related enzymes [58]. In the same study, epigenomic analyses of human kidney tissue identify an injury-sensitive regulatory region within the PCK1 locus, containing predicted HNF4α-positive and SOX9-negative regulatory elements [58]. This region shows persistent dedifferentiation, reduced chromatin accessibility, and enrichment of repressive histone marks in acute kidney injury (AKI) and CKD, consistent with transcriptional silencing of PCK1 in failed repair state [58].

Beyond PCK1 enzyme, the expression of other key gluconeogenic is altered in kidney disease [57]. PC expression has been reported to be reduced in human kidney biopsies from patients with fibrotic CKD and correlated with renal function and fibrosis burden [59]. Similarly, FBP1 expression is reduced in diabetic kidney disease (DKD), and transcriptomic studies indicate that lower FBP1 levels are associated with fibrosis severity and renal functional decline [60]. Consistently, a recent study integrating urinary and renal single-cell data with machine learning identified a three-gene urinary signature, including FBP1 with strong diagnostic performance for DKD [61].

Functional evidence in humans remains limited, as complete loss of some essential gluconeogenic enzymes is likely incompatible with life. In a large genome-wide association study of kidney function (eGFR), PCK1 locus was identified as a potential interesting region [62]. Complementing this observation, glycogen storage disease type Ia (GSDI), a disorder caused by G6PC deficiency, is associated with CKD and polycystic kidney features have been described in GSDI cohorts [63, 64] (Table 1).

Together, these findings indicate that gluconeogenesis loss is strongly associated with renal disease progression in human CKD, with some argument for a contribution to progression of the phenotype.

Mouse data

Recent single-cell, epigenomic, and spatial metabolomic studies in various experimental AKI and CKD models, including both diabetic and nondiabetic, corroborate key features observed in human and demonstrate profound PT metabolic reprogramming characterized by reduced oxidative phosphorylation, acquisition of a glycolytic phenotype, and suppression of gluconeogenic gene expression [43, 50, 51, 65, 66].

Furthermore, in mice models, suppression of gluconeogenesis is not a uniform response to injury but is tightly coupled to epithelial repair outcomes. In PTECs undergoing adaptive repair, injury-induced transcriptional programs are transient and followed by re-establishment of differentiated epithelial states, whereas in failed repair the injury signature persists alongside sustained repression of oxidative and gluconeogenic pathways [58]. Profibrotic signaling pathways, particularly transforming growth factor-beta (TGF-β), which is well known to suppress epithelial gene programs and amplify inflammatory and fibrotic responses in CKD, may further reinforce this transcriptional environment [56, 58]. Similarly, to what has been observed in human, Pck1 expression is regulated by HNF4α, a key activator of gluconeogenic genes that directly binds the Pck1 promoter [58, 67]. In addition, the epithelial transcription factor Sox9, which is reactivated in renal tubular cells during injury and repair, participates in transcriptional networks that can influence metabolic gene expression, including gluconeogenic pathways [68].

Consistent with this framework, disease states characterized by profound epithelial metabolic rewiring exhibit features incompatible with sustained PT gluconeogenesis, mirroring observations in humans.

Gluconeogenesis loss as a causal mechanism in CKD progression in mice models

Functional and metabolomic studies in mouse directly support the idea that injury-associated changes in gluconeogenic gene and protein expression translate into reduced pathway activity and broader disruption of mitochondrial metabolic flux [43, 50]. Mechanistic work further indicates that suppression of PT gluconeogenesis is not merely correlative but can contribute to disease progression.

Loss of gluconeogenic capacity in mice is associated with bioenergetic stress and a shift toward glycolytic reprogramming with paracrine consequences [43, 50, 51]. Increased glycolytic flux and lactate production by injured PT act as metabolic cues that promote activation of interstitial fibroblasts. In AKI mouse models, tubule-derived lactate is required for fibroblast activation and proliferation [69]. Elevated lactate may further sustain fibrosis through histone and nonhistone lactylation, supporting fibrogenic transcriptional programs [70]. Therefore, the loss of gluconeogenic capacity impairs mitochondrial metabolism but also fuels a profibrotic microenvironment.

Notably, genetic deletion or restoration of individual gluconeogenic enzymes in mice models has yielded key insight into their roles in renal homeostasis and injury. Below, we summarize key findings, from loss or gain of functions, studies obtain in experimental models.

PHOSPHOENOLPYRUVATE CARBOXYKINASE 1

In mice, tubule-specific deletion of Pck1 impairs TCA cycle cataplerosis, reduces mitochondrial respiration and ATP production, and increases susceptibility to metabolic acidosis and tubular injury [43, 50]. Pck1-tubular-specific deletion is also associated with defective ammoniagenesis and reduced renal gluconeogenesis, linking this enzyme to both acid–base regulation and energy homeostasis [50] (Table 1). In a diabetic nephropathy model, PT-specific Pck1 conditional knockout (CKO) leads to tubular injury, increased apoptosis, albuminuria, and progressive tubulointerstitial fibrosis. Renal fibrotic changes in CKO mice were associated with mitoribosomal defects and dysfunction, resulting in impaired mitochondrial protein translation and oxidative phosphorylation [52]. Complementary studies demonstrate that PCK1-mediated cataplerosis is required for maintaining mitochondrial fitness; its loss disrupts TCA flux, impairs oxidative phosphorylation, induces structural mitochondrial damage, and worsen AKI severity while accelerating CKD progression in different nondiabetic kidney disease models [43] (Table 1).

Conversely, restoring PCK1 expression in the kidney is sufficient to mitochondrial integrity and mitigated fibrosis and tubular injury in both diabetic and nondiabetic experimental CKD models, indicating the major role of this enzyme during renal disease [43, 50, 52, 56] (Table 1). Similarly, restoration of PCK1 in a mouse model of IgA nephropathy attenuates TGF-β-driven inflammatory and fibrotic signaling in glomerular mesangial cells exposed to polymeric IgA1 [56] (Table 1). These findings extend the relevance of PCK1 beyond canonical gluconeogenesis and support its therapeutic potential in distinct forms of kidney disease.

PYRUVATE CARBOXYLASE

PC, long recognized as the principal anaplerotic enzyme replenishing TCA cycle intermediates, is functionally required for tubular metabolic integrity. In a mouse model, PT-specific Pcx deletion induces mitochondrial damage, activates the sulfide:quinone oxidoreductase (SQOR)–cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) axis, drives glycolytic reprogramming, and causes marked interstitial fibrosis [59] (Table 1). These findings are consistent with the established role of PC in maintaining TCA cycle flux and preventing energy failure [71, 72].

GLUCOSE-6-PHOSPHATASE

Impairment of the terminal gluconeogenic step mediated by G6PC produces marked and progressive renal phenotypes. In mice, kidney-specific G6pc deletion induces glucose-6-phosphate accumulation, mitochondrial dysfunction, oxidative stress, and progressive tubulointerstitial disease [19] (Table 1). In longer-term models, kidney-specific G6pc deletion leads to interstitial fibrosis and glomerulosclerosis followed by the development of polycystic kidneys and late-stage renal failure, highlighting the progressive nature of this metabolic nephropathy [64]. Consistent with the link between G6PC signaling and mitochondrial integrity, recent work identified the circular RNA circG6pc as a protective regulator that attenuates oxidative stress and mitochondrial damage through the miR-7018–5p/Aldh6a1 axis in models of kidney fibrosis [73].

Disease specificity across nephropathies

Increasing omics evidence indicates that suppression of PT gluconeogenesis is a recurring metabolic feature across diverse kidney diseases rather than a lesion restricted to diabetic nephropathy. Human transcriptomic studies across multiple kidney diseases, including ischemic AKI and progressive CKD such as DKD, autosomal dominant polycystic kidney disease (ADPKD), proteinuric nephropathies, and immune-mediated glomerulopathies, report reduced expression of gluconeogenic enzymes PCK1, FBP1, and G6PC in association with tubular dedifferentiation and fibrosis severity [51, 52, 54, 56, 60, 63, 64]. Importantly, the magnitude and timing of this suppression appear to be context- and stage-dependent, consistent with dynamic metabolic rewiring during injury and repair. Consistent with these human observations, experimental mouse studies provide mechanistic support that perturbing PT gluconeogenic machinery can influence disease progression in different models of renal disease such as proteinuric CKD, AKI to CKD transition, DKD, and IgA nephropathy, for example.

Together, these observations support the hypothesis that impaired PT gluconeogenic capacity reflects a shared tubular metabolic response characterized by disruption of the differentiated PT program and altered mitochondrial metabolic homeostasis, rather than a disease-specific signature.

Clinical relevance and therapeutic modulation

Metabolic modifications of the PT are increasingly recognized as a clinically relevant axis in kidney disease, raising the possibility that renal gluconeogenic metabolism may be modified by current nephroprotective therapies.

Accumulating experimental and translational evidence indicates that SGLT2 inhibition improves PT oxidative metabolism and partially reverses injury-associated metabolic reprogramming, with an important modulation of gluconeogenic gene expression [74, 75]. Restoration of tubular metabolic competence may therefore represent one mechanism contributing to nephroprotection. However, direct measurement of renal gluconeogenic flux in treated human kidneys is lacking, and whether enhanced gluconeogenesis specifically or other metabolic pathways mediate clinical benefit of SGLT2 inhibition remains to be established.

Similarly, ketogenic states and ketone bodies have been shown in experimental models to stimulate renal gluconeogenesis and support metabolic adaptation of PTECs, providing a mechanistic rationale for potential nephroprotective effects [76]. While emerging studies suggest feasibility in selected CKD populations, definitive evidence demonstrating restoration of tubular gluconeogenic capacity and clinically meaningful nephroprotection is still lacking.

Glucagon-like peptide-1 (GLP-1) receptor agonists represent another class of therapies with established cardiorenal benefits. Although, preclinical studies and mechanistic review support multiple renal actions of these agents, evidence for a direct modulation of tubular gluconeogenic pathways is limited. Their protective effects in humans likely reflect predominantly systemic and hemodynamic effects [77].

Together, these observations underscore the potential translational importance of renal gluconeogenesis and underscore the need for dedicated human and experimental studies, integrating tissue-resolved and metabolomic approaches during different nephroprotective therapies, as well as more selective kidney-targeted pharmacological strategies to modulate the gluconeogenesis pathway and establish its therapeutic potential.

CONCLUSION

Renal gluconeogenesis emerges from this body of work as a central metabolic function of the PT, extending far beyond its classical role in glucose production. In physiological conditions, the kidney contributes dynamically to systemic glucose homeostasis by compensating for declining hepatic output during fasting and stress, a process enabled by hepatorenal reciprocity. At the same time, renal gluconeogenesis is tightly coupled to ammoniagenesis, positioning the kidney as a major regulator of systemic acid–base balance. Beyond glucose and pH regulation, renal gluconeogenesis plays a fundamental role in maintaining mitochondrial function. By sustaining TCA dynamics through anaplerosis and cataplerosis—most notably via PCK1-mediated carbon flux—gluconeogenesis preserves oxidative metabolism, ATP production, and mitochondrial integrity in PTECs. This metabolic architecture allows the kidney to meet its exceptionally high energetic demands while maintaining epithelial differentiation and functional resilience.

In kidney disease, however, this finely tuned system is progressively dismantled. Suppression of gluconeogenesis appears to occur within a broader metabolic rewiring toward glycolysis that accompanies epithelial dedifferentiation, mitochondrial dysfunction, and fibrotic remodeling. While this shift may initially reflect an adaptive response to injury or hypoxia, accumulating evidence indicates that loss of gluconeogenic capacity has deleterious consequences.

AUTHORS’ CONTRIBUTIONS

S.S. (Writing – original draft & editing, Data curation, Visualization), T.V. (Writing – review & editing), D.D. (Writing – review & editing), and S.d.S. (Writing – review & editing, Data curation, Funding).

CONFLICT OF INTEREST STATEMENT

None declared.

FUNDING

S.d.S. is supported by the Swiss National Science Foundation (320030_204187 and 320030-236128). D.D. is the recipient of a grant from the Swiss National Science Foundation (32350_214547).

DATA AVAILABILITY STATEMENT

No new data were generated or analysed in support of this research.