Eric Féraille

Aim: Renal sodium reabsorption occurs through both transcellular and paracellular pathways. Tight junction proteins play a key role in mediating paracellular transport. The collecting duct is critical for the fine tuning of sodium balance and is highly responsive to changes in dietary salt intake. This study aimed to determine whether a low‐sodium diet modulates paracellular sodium permeability by regulating the expression or localization of claudin‐3, a major tight junction protein in the collecting duct. Methods: Wild‐type and claudin‐3 knockout male mice were fed low (0.01%) or normal (0.18%) sodium diets for 7 days, with or without treatment with spironolactone, a mineralocorticoid receptor antagonist. The expression of tight junction proteins was analyzed by immunoblotting and immunofluorescence. Functional effects of claudin‐3 on ion permeability were evaluated in cultured mouse collecting duct principal cells using chamber recordings after claudin‐3 overexpression or gene silencing. Results: Low‐sodium diet increases claudin‐3 expression in mouse kidneys. In cultured cells, aldosterone enhanced claudin‐3 abundance and its plasma membrane localization. Claudin‐3 overexpression reduced, while its silencing increased paracellular permeability to sodium and chloride. Claudin‐3 knockout mice on a low‐sodium diet compensated by upregulating epithelial sodium channel subunits, claudin‐4, claudin‐8, and claudin‐10. This adaptive response persisted under mineralocorticoid receptor blockade. Conclusions: Our findings demonstrate that aldosterone strengthens the paracellular sodium barrier in the collecting duct by inducing claudin‐3. In the absence of claudin‐3, compensatory regulation of other claudins and sodium transporters preserves sodium homeostasis under low‐salt conditions, thus revealing adaptive mechanisms in renal sodium handling.

Purpose of review: Tight junctions formed by claudins regulate paracellular permeability to sodium, chloride, calcium, magnesium, and water along the nephron, thereby enabling energy-efficient reabsorption of glomerular filtrate that limits tubular oxygen consumption. Recent findings: We review evidence from knockout models, cell lines, and single-cell analyses demonstrating highly segment-specific claudin functions along the nephron. In the proximal tubule, independent claudin-2 and claudin-10a pores mediate cation/water and anion permeability, respectively, and inducible claudin-2 deletion causes hypercalciuria and nephrocalcinosis. In the thick ascending limb, three functionally distinct cell populations express different claudin combinations, with claudin-10b driving paracellular Na ⁺ permeability and claudin-16/19 mediating Ca ²⁺ and Mg ²⁺ reabsorption. In the aldosterone-sensitive distal nephron, coupling between ENaC-ɣ and claudin-8 links transcellular Na ⁺ entry to the prevention of paracellular Na ⁺ back-leak independently of aldosterone, whereas aldosterone transcriptionally upregulates claudin-3 and claudin-8. Claudin-3 deficiency triggers compensatory upregulation of ENaC and claudins-4/8/10 to preserve sodium balance. Claudin-4 is upregulated in nephrotic syndrome and promotes NaCl retention. These findings reveal paracellular pathway's critical role in metabolic efficiency and tubulopathy pathogenesis Summary: Claudins form segment-specific paracellular pathways that enable efficient ion and water reabsorption with low metabolic cost along the nephron. Mutations with loss of function of claudins cause tubulopathies with salt loss, hypomagnesemia, and/or nephrocalcinosis and kidney stones. Future studies using inducible and segment-specific models will be essential to identify strategies to restore paracellular transport in kidney disease.

Background: Renal sodium reabsorption occurs via both transcellular and paracellular pathways. Tight junction proteins play a key role in mediating paracellular transport. The collecting duct (CD) is critical for the fine-tuning of Na ⁺ balance and is sensitive to changes in dietary salt intake. A low-sodium diet, which increases endogenous aldosterone secretion, stimulates transcellular sodium transport via epithelial Na ⁺ channels (ENaC) and Na,K-ATPase. We hypothesized that a low-sodium diet also modulates paracellular Na ⁺ permeability by regulating the expression or function of claudin-3, a major tight junction protein in the CD, in order to limit the back-leak of reabsorbed sodium and preserve sodium balance. Methods: We used in vivo mouse models and cultured mouse CD principal cells (mCCD _cl1 ) to assess aldosterone’s effects on tight junction proteins. In mCCD _cl1 cells, aldosterone-induced changes in claudin-3 expression and localization were evaluated via Western blotting and immunofluorescence, and Ussing chamber assays were used to assess paracellular Na ⁺ and Cl ⁻ permeability after modulating claudin-3 expression. Wild-type and claudin-3 knockout mice were fed low (0.01%) or normal (0.18%) sodium diets for seven days. In subsets of low sodium diet mice, spironolactone (a mineralocorticoid receptor antagonist) was administered. Results: In mice, a low-sodium diet upregulates renal claudin-3 expression. Concordantly, in vitro studies using mCCD _cl1 cells showed that aldosterone treatment increased claudin-3 protein levels and promoted its localization to the lateral membrane. Functional analyses demonstrated that claudin-3 overexpression reduced paracellular permeability to both Na ⁺ and Cl ⁻ , while claudin-3 silencing increased it. Claudin-3 knockout mice subjected to a low-sodium diet exhibited compensatory upregulation of the α- and γ-subunits of ENaC, alongside increased expression of claudin-4, claudin-8, and claudin-10. This highlights an adaptive response that maintains sodium homeostasis in the absence of claudin-3. Importantly, this compensatory mechanism persists even under spironolactone treatment, suggesting that the adaptation of claudin-3-deficient mice occurs independently of mineralocorticoid receptor activation. Conclusions: Our findings demonstrate that aldosterone enhances claudin-3 expression, reinforcing the paracellular barrier to Na ⁺ and complementing its classical role in transcellular Na ⁺ transport. Under low-sodium conditions, claudin-3-deficient mice adapt through complementary mechanisms aimed at increasing sodium reabsorption via ENaC activation and upregulation of claudin-4 and claudin-8, both barrier-forming claudins that restrict paracellular sodium leakage in the CD. This is associated with increased claudin-10 abundance in the thick ascending limb of Henle, a pore-forming claudin that facilitates paracellular sodium permeability. This study advances our understanding of the complex control of renal sodium handling, revealing adaptive mechanisms in response to low-salt diet and claudin-3 deficiency.

Excessive dietary salt intake is a global health concern, affecting cardiovascular, renal, and bone health. While the renin-angiotensin-aldosterone system (RAAS) is a known regulator of dietary salt-induced hormonal responses, the impact of adrenal cortisol remains unclear. Here, we performed a retrospective analysis in individuals (n=292) consuming a random diet. Dietary salt intake positively correlated with urinary cortisol and inversely correlated with plasma fibroblast growth factor 23 (FGF23), a bone-derived hormone regulating phosphate and vitamin D homeostasis. Controlled salt diets in healthy individuals confirmed a dose-dependent increase in urinary cortisol and suppression of plasma FGF23. In mice, oral corticosterone, a cortisol analogue, reduced circulating FGF23 levels. RNA-seq analysis of corticosterone-treated MC3T3 osteoblasts identified suppression of FGF23 via glucocorticoid receptor activation, anti-inflammatory pathways, and reduced osteoblast activity. Our findings reveal a novel endocrine cascade where high salt intake elevates cortisol and suppresses FGF23, with potential implications for bone, kidney, and cardiovascular health. SIGNIFICANCE STATEMENT: Excessive dietary salt intake is a global health concern with poorly understood hormonal consequences beyond the renin-angiotensin-aldosterone system. Here, we identify a novel endocrine cascade in which high salt intake elevates cortisol signaling and suppresses fibroblast growth factor 23 (FGF23), a bone-derived hormone central to phosphate and vitamin D homeostasis. These findings are supported by a human cohort on random diets, a controlled dietary salt intervention, and corticosterone experiments in mice and osteoblasts. Mechanistically, cortisol suppresses FGF23 via glucocorticoid receptor activation, anti-inflammatory signaling, and repression of osteoblast activity. These findings have potential implications for bone, kidney, and cardiovascular health, and suggest that dietary salt intake may influence the clinical interpretation of cortisol and FGF23 measurements.

The knock-out of paracingulin (CGNL1) prevents the development of hypertension in a unilateral nephrectomy/angiotensin II infusion model (N+A) in mice and this antihypertensive effect likely depends on uncoupling of angiotensin II from stimulation of sodium transporter activity in kidney tubules rather than on alteration of resistance blood vessel contractility.

Our study reveals an increase in ERMP1 expression in acute and chronic kidney diseases, potentially serving as a protective mechanism against excessive ER stress. Conversely, a decline in ERMP1 expression in the kidney exacerbates age-related chronic kidney disease. Overall, the study enhances our understanding of the role of ERMP1 in kidney pathophysiology, paving the way for future research and therapeutic developments aimed at improving outcomes for patients with kidney diseases.

Chronic kidney disease (CKD) is a growing public health crisis, affecting over 10% of the global population and significantly increasing mortality and morbidity. Irrespective of its underlying cause, tubulointerstitial fibrosis (TIF) is a hallmark of CKD progression, with myofibroblasts being the primary effectors of renal fibrosis. Here, we show that 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a critical driver of pathogenic myofibroblast differentiation and fibrosis in CKD. Using genetic deletion and pharmacological inhibition of 11β-HSD1 in mouse models, we demonstrate a marked reduction in TIF severity and improved renal function, linked to the suppression of a regulatory myofibroblast (Reg-MF) subpopulation. Single-cell and spatial transcriptomics data reveal that 11β-HSD1 is essential for the activation and expansion of Reg-MFs, which is conserved across species and predicts worse outcomes in CKD patients and kidney allograft recipients. These findings establish a direct link between 11β-HSD1 activity and renal fibrogenesis, highlighting its role during the transition from pericytes to pathogenic Reg-MFs. Our results support 11β-HSD1 inhibition as a promising therapeutic strategy to mitigate CKD progression, offering both mechanistic insights and translational potential for improving patient outcomes.

Cingulin (CGN) and paracingulin (CGNL1) are cytoplasmic proteins of tight junctions (TJs), where they play a role in tethering ZO-1 to the actomyosin and microtubule cytoskeletons. The role of CGN and CGNL1 in the barrier function of epithelia is not completely understood. Here, we analyzed the effect of the knock out (KO) of either CGN or CGNL1 or both on the paracellular permeability of monolayers of kidney epithelial (MDCK) cells. KO cells displayed a modest but significant increase in the transepithelial resistance (TER) of monolayers both in the steady state and during junction assembly by the calcium switch, whereas the permeability of the monolayers to 3 kDa dextran was not affected. The permeability to sodium was slightly but significantly decreased in KO cells. This phenotype correlated with slightly increased mRNA levels of claudin-2, slightly decreased protein levels of claudin-2, and reduced junctional accumulation of claudin-2, which was rescued by CGN or CGNL1 but not by ZO-1 overexpression. These results confirm previous observations indicating that CGN and CGNL1 are dispensable for the barrier function of epithelia and suggest that the increase in the TER in clonal lines of MDCK cells KO for CGN, CGNL1, or both is due to reduced protein expression and junctional accumulation of the sodium pore-forming claudin, claudin-2.