Daily body clock and stress hormone patterns in the kidney support structure

The physiological functions of the kidney, including glomerular filtration, tubular reabsorption, solute transport, and urinary excretion, exhibit strong circadian patterns that align with the body’s rest-activity cycle [1–3]. These rhythms are regulated by molecular clocks involving core clock genes including brain and muscle ARNT-like protein 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), Period proteins (PER), and Cryptochrome proteins (CRY) within kidney cells [4–6]. While circadian regulation of kidney function has become increasingly recognised, recent evidence indicates that these molecular clocks also direct the timing of matrix remodelling [7–9]. This introduces a new conceptual framework where the kidney matrisome is not only dynamic, but also temporally coordinated, to match the physiological and regenerative demands of the kidneys [1]. Understanding how circadian clocks regulate kidney matrix components, remodelling, and repair processes could uncover new insights into kidney disease progression and therapeutic targets. This review summarises emerging studies linking circadian regulation to glomerular matrix dynamics, including rhythmic gene expression in podocytes and the basement membrane, the role of glucocorticoids (GCs) in clock entrainment, and interactions between matrix stiffness and cellular clocks. It also explores the mechanisms and possible therapies, such as chronotherapy and treatments targeting the clock.

The kidney matrix is regionally specialised across nephron segments and the interstitium (Fig. 1a). The initial segment of the nephron is the glomerulus, a spherical bundle of fenestrated capillaries which collectively function as a complex sieve, selectively filtering blood across the glomerular filtration barrier. These highly specialised filters are of particular importance clinically, given that most cases of chronic kidney disease (CKD) occur secondary to glomerular pathology [10]. The filtration barrier is comprised of three interacting layers: the inner fenestrated endothelial cells, a middle protein mesh that forms the glomerular basement membrane (GBM), and an outer visceral podocyte layer (Fig. 1b). The GBM is a highly organised meshwork of type IV collagen heterotrimers (α3–α4–α5), along with laminins (mainly α5β2γ1), nidogens, and heparan sulphate proteoglycans [11]. Pathogenic variants in COL4A3, COL4A4, or COL4A5 cause Alport syndrome, the most common monogenic cause of kidney disease in childhood [12, 13]. The mesangial matrix, enriched in type IV, V, and VI collagens and fibronectin, surrounds glomeruli and reinforces the capillary tuft [10, 14].

Along the nephron tubules, segment-specific epithelial basement membranes, composed of unique collagen IV and laminin isoforms, support both reabsorptive and secretory functions [19, 20]. These are encased by the interstitial matrix, particularly abundant in the cortex and medulla, which contains fibrillar collagens I and III, elastin, fibronectin, and matricellular proteins. This compartment also harbours fibroblasts and immune cells, serving as a signalling hub for matrix remodelling [21]. Enzymes, such as matrix metalloproteinases and their tissue inhibitors, dynamically regulate matrix turnover in response to both physiological and pathological stimuli [22]. Together, the GBM, tubular basement membranes, and interstitium form a spatially defined kidney matrisome that preserves architecture, adapts to stress, and is temporally regulated by circadian clock genes, which coordinate anabolic and catabolic activities [2, 15, 23, 24].

Mammalian circadian rhythms are intrinsic 24-h oscillations that synchronise cellular and physiological processes with environmental cycles (Fig. 2). These rhythms are organised by a hierarchical network of central and peripheral clocks, with the suprachiasmatic nucleus in the hypothalamus serving as the master pacemaker [25, 26]. Peripheral clocks, present in nearly all tissues, including the kidney, are entrained by central cues and local signals such as feeding, hormones, and temperature [27]. At the cellular level, circadian timing arises from a core transcription translation feedback loop. In the primary loop, the proteins CLOCK and BMAL1 form a heterodimer that binds to specific DNA motifs known as enhancer box elements to activate transcription of the Per1–3 genes and Cry1 and Cry2 genes. As PER and CRY proteins accumulate, they move into the nucleus and inhibit CLOCK:BMAL1 activity, completing the negative feedback cycle. A second regulatory loop stabilises this system: the nuclear receptors REV-ERB and ROR repress or activate Bmal1 transcription by binding to response elements in its promoter, thereby shaping rhythm amplitude and phase [28]. Post-translational processes provide additional control, as casein kinases and phosphatases regulate PER and CRY phosphorylation, degradation and nuclear entry, ensuring accurate ∼24-h oscillations [29–31]. Together, these coupled loops generate rhythmic expression of large gene networks across tissues.

Disruption of circadian timing, whether through genetic variants or environmental factors, is increasingly recognised as a contributor to kidney dysfunction (Fig. 1b). Modern behaviours such as shift work, irregular sleep, and chronic exposure to artificial light desynchronise internal clocks from external cues, impairing rhythmic gene expression and physiological processes that sustain kidney homeostasis cues [36–39].

Animal studies have demonstrated that the disruption of core clock genes, including Clock and Bmal1, alters the kidneys’ response to stress [2, 16, 24, 40]. In some settings, this reduces fibrosis, likely through antioxidant pathways such as glutathione metabolism [24]; however, such effects reflect a broader loss of physiological regulation. Environmental perturbations, including phase shifts or altered light cycles, further impair circadian control of kidney function. Even mild nocturnal light exposure disturbs excretory rhythms, blood pressure regulation, and hormonal signalling, particularly in models predisposed to hypertension or metabolic stress [38, 39, 17].

In humans, chronic circadian misalignment is most evident in night shift workers and individuals with irregular schedules. Cohort studies associate long-term night work with systemic inflammation, albuminuria, and accelerated decline in kidney function [41, 42]. These risks are compounded by fragmented sleep, poor dietary timing, and melatonin suppression [42, 43]. Although some adaptation occurs, complete physiological alignment is rarely achieved [41]. Diet also exerts a strong circadian influence on sodium excretion and blood pressure displaying predictable daily rhythms in healthy individuals [44]. These become blunted in hypertension and CKD, contributing to nocturnal hypertension and increased cardiovascular risk [45, 46]. Furthermore, high-salt or high-fat diets alter kidney clock gene expression in rodents, amplifying oxidative stress and accelerating kidney injury [47–50].

These insights highlight therapeutic opportunities to restore circadian alignment. Among these, GCs are particularly notable, as they function both as systemic circadian entrainers and as frontline therapy in glomerular disease [51, 52].

GC therapy remains the cornerstone of treatment for glomerular disease, although its mechanisms of action are incompletely defined [51, 52]. Beyond immunosuppression, GCs act directly on podocytes to stabilise the actin cytoskeleton, remodel the glomerular matrix, and modulate circadian signalling [53]. In cultured murine podocytes, dexamethasone protects against puromycin aminonucleoside injury by increasing polymerised actin, preserving cytoskeletal structure, and accelerating recovery [53]. These effects are mediated through activation of RhoA GTPase, which promotes actin assembly, and suppression of Rac1, which limits podocyte motility and reinforces barrier stability [54]. At the transcriptional level, podocytes express a functional GR complex. GC exposure induces canonical GR-responsive genes, such as FKBP51 and αB-crystallin, drives receptor phosphorylation and nuclear translocation, and directly regulates cytoskeletal and matrix pathways [54, 55]. Transcriptomic studies further show that GCs normalise matrix-related gene expression. In a rat model of nephrotic syndrome, both GCs and the PPAR-γ agonist pioglitazone reversed dysregulation of ADAM12, COL1A1, and SERPINE1 – genes implicated in human FSGS and minimal change disease [56]. These changes were most pronounced in podocytes and mesangial cells, highlighting matrix remodelling as an early therapeutic target and suggesting shared transcriptional footprints among agents that restore glomerular homeostasis. Importantly, recent evidence links these effects to circadian regulation [15]. Podocyte disease genes implicated in steroid-resistant nephrotic syndrome acquired rhythmicity with GC treatment, whereas disruption of the podocyte clock altered their expression [15]. This connection reveals an interplay between the glomerular clock and GC signalling, providing new insight into GC resistance mechanisms. GCs also function as systemic circadian entrainers [15]. In podocytes, they reinforce rhythmic transcriptional programs critical for barrier integrity [15]. Matrix-derived cues further shape these rhythms: stiffness and substrate tension modulate clock gene expression via integrin-mediated adhesion and signalling pathways, including RhoA-ROCK and YAP-TAZ [57, 58]. For instance, increased stiffness enhances YAP/TAZ nuclear activity and cytoskeletal remodelling [57], while the disruption of RhoA regulators, such as ARHGAP29, alters adhesion and podocyte morphology [58]. Together, these observations suggest that GC efficacy is not solely dose-dependent but also time-dependent. Administering GCs at circadian phases that support cytoskeletal reinforcement and matrix repair may enhance therapeutic benefit, while mistimed dosing could contribute to suboptimal responses.

Circadian regulation of the kidney matrisome has direct implications for disease mechanisms and therapy. In glomerular diseases, including Alport syndrome and glomerulonephritis, progressive fibrosis and matrix accumulation drive functional decline [11, 16, 32]. Experimental and clinical studies demonstrate that circadian disruption exacerbates kidney outcomes, whereas rhythm stabilisation is protective [2, 15, 37, 59]. Aligning behaviours such as eating, sleeping, and light exposure with circadian timing may help preserve matrix balance and prevent fibrosis [45, 60, 61]. Conversely, CKD exacerbates circadian disruption through uremic toxins and inflammation, reinforcing a cycle of kidney and clock dysfunction [43, 62].

Chronotherapy offers a framework for synchronising treatment with biological rhythms [63, 64]. Matrix-related pathways peak at defined times [15], suggesting that antifibrotic therapies may be most effective when delivered during phases of fibrogenic activity [65, 66]. Clinical evidence supports this approach. That is, bedtime dosing of antihypertensives restores nocturnal dipping and reduces proteinuria [67–69]. Similarly, angiotensin-converting enzyme inhibitors, pirfenidone, and GCs may yield greater benefits when administered in alignment with the circadian rhythm [15, 70–72]. Even dialysis timing could be optimised to support hormonal and metabolic rhythms [73, 74].

Targeting the molecular clock itself represents another avenue [75–78]. Stabilising BMAL1 preserves antioxidant and antifibrotic activity in kidney cells [40]. Small molecules, such as REV-ERB agonists and casein kinase inhibitors, modulate clock amplitude and phase, and preclinical studies have reported reduced fibrosis in kidney tissue [78–80]. To minimise off-target effects, kidney-targeted delivery systems, including nanoparticles, are being explored for localised therapy [81–83].

Circadian control of the kidney matrisome influences both healthy ageing and the progression of CKD. Defining matrix rhythms across nephron segments and how they are altered in pathology may reveal new opportunities for intervention. A key unanswered question is how clocks in podocytes, mesangial cells, and tubular epithelia coordinate to maintain matrix homeostasis, and whether loss of synchrony among these cell types promotes fibrosis. Using circadian biomarkers and optimising treatment timing to restore alignment between systemic and kidney clocks may help protect kidney function.

The authors have no conflict of interest.

This research was primarily funded by a Wellcome PhD studentship to C.G. (Ref: 317456/Z/24/Z). R.L. is funded by Kidney Research UK and The Stoneygate Trust (Alport Research Hub), the Wellcome Trust (Ref: 226804/Z/22/Z, Ref: 227417/Z/23/Z, and Ref: 301803/Z/23/Z), and the NIHR Manchester Biomedical Research Centre (NIHR203308). R.P. is funded with a National Institute for Health Research Clinical Lectureship.

C.G., R.L., and R.P. jointly conceived the review topic and scope. C.G. conducted the primary literature search and prepared the first draft. R.L. and R.P. contributed to writing, critical revision, and interpretation of the literature. All authors reviewed and approved the final manuscript.