Biology subjects

Wagner, C. A.

Publications and source records attributed to Wagner, C. A..

6 recordsLinked to original sources

bioRxiv2026

Serum proteomic atlas reveals distinct molecular signatures of lupus nephritis activity, chronicity, and treatment response

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE), features heterogeneous renal pathology and reliance on invasive biopsies for diagnosis, prognosis, and treatment selection. Current peripheral clinical markers inadequately capture disease activity and progression. Here, we performed comprehensive serum proteomic profiling of over 5,000 proteins in the large, longitudinal Accelerating Medicines Partnership Rheumatoid Arthritis/SLE cohort of 270 LN patients and 63 healthy controls. Machine learning identified distinct molecular signatures that classified LN versus controls, differentiated histological classes, and delineated activity- and chronicity-associated pathways, including inflammatory cytokine, PI3K/AKT, TGFb, and complement/coagulation pathways. An increase in VSIG4, CD27, HAVCR1, and LAIR1 consistently emerged as top biomarkers across multiple clinical contexts, and early decreases in these markers at 3 months were associated with complete treatment response at 1 year. By resolving coordinated serum protein modules linked to key inflammatory, PI3K/AKT, TGFb, and complement pathways, these signatures mechanistically connect circulating proteomic perturbations to intrarenal immune activation, tissue injury, and repair in LN. These findings demonstrate that serum proteomics reflect complex intrarenal immunopathology and offer a promising noninvasive "liquid biopsy" approach to refine LN classification and guide personalized management, potentially reducing the need for repeated invasive biopsies and improving therapeutic decision-making.

immunology↗

bioRxiv2024

Acid excretion is impaired in calcium oxalate stone formers

BackgroundUrine pH is a key factor in kidney stone formation. We aimed to identify whether acid excretion capacity is disturbed in calcium oxalate (CaOx) or calcium phosphate (CaP) stone formers. MethodUrinary, serum, clinical, and anthropomorphic baseline data were obtained from the Swiss Kidney Stone Cohort, a prospective, longitudinal, and multi-centric observational study. We included in this study 193 non-stone formers (NSF, confirmed by negative CT scan), and 309 CaOx and 28 CaP stone formers. Titratable acids, net acid excretion (NAE), NAE capacity (NAEC) and acid-base (AB) score were calculated. Logistic regression analyses were used to estimate the potential associations of various acid-base variables with the occurrence of CaOx kidney stones. ResultsCaOx stone formers showed a disturbed capacity to excrete acids in comparison to NSF (NAEC NSF = 3.49{+/-}12.6 mmol/24h; CaOx = -1.06{+/-}13.10; CaP = 0.97{+/-}14.70 and AB score NSF = 20.5{+/-}6.36 mmol/24h; CaOx = 17.9{+/-} 6.53; CaP = 18.8{+/-}6.10). The correlation between urine calcium and urine pH was altered in CaOx stone formers and between urine calcium and NAE was stronger in CaP stone formers. Logistic models showed that urinary ammonium was negatively associated with CaOx stone formation (unadjusted model, odds ratio 0.43[0.32-0.58], p< 0.001 for CaOx). Urine calcium was positively associated with CaOx kidney stones (2.85 [2.11-3.92], p<0.001). Similar results were obtained after adjusting for age, sex, and BMI. Replacing urine ammonium, pH, and phosphate with NAEC or ammonium and pH with AB score in our logistic regression models showed that NAEC and AB score are strongly associated with CaOx kidney stone formation. ConclusionAmmonium excretion, NAEC and AB score are associated with the occurrence of CaOx kidney stones suggesting a potential role of proximal tubule dysfunction in their formation. CaP stone formers exhibit a disproportionately higher calcium excretion when acid excretion increases. Key learning pointsO_ST_ABSWhat was knownC_ST_ABSUrine pH is a strong determinant in the formation of various urologically relevant crystals. Impaired urine acidification capacity has been observed in individuals who form calcium phosphate and uric acid stones. This study addsWhen compared to non-stone formers, calcium oxalate stone formers are marked by a reduced capacity of excreting acids when urine pH becomes more acidic. Potential impactThe calculation of net acid excretion capacity and acid-base score are novel tools to identify those under potential higher risk of developing calcium oxalate stones.

physiology↗

bioRxiv2023

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that has recently received much attention due to its association with the progression of chronic kidney disease, cardiovascular disease, and associated mortality. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (low serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell line UMR-106. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. On the other hand, arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+] revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that human hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis. SIGNIFICANCE STATEMENTFibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls phosphate and vitamin D metabolism. Excess FGF23 is postulated to cause left ventricular hypertrophy, while FGF23 deficiency reduces life span and mimics age-related diseases in mice. FGF23 is also a potential biomarker for chronic kidney disease and cardiovascular disorders, but its role in disease progression is unclear. Therefore, it is important to explore the regulation of FGF23 production, which is incompletely understood. Our paper identifies extracellular-sodium-NFAT5 signaling as a key regulator of FGF23 formation.

physiology↗

bioRxiv2022

Claudin-4, a core component of the tight-junctional complex along the collecting system, is induced in nephrotic syndrome

BackgroundNephrotic syndrome (NS) is characterized by massive sodium chloride retention. Along the kidney tubule, sodium and chloride reabsorption are coupled via a combination of transcellular and paracellular transport pathways. The mechanism of sodium retention in NS has been extensively studied, but the associated chloride transport pathway has not been elucidated. MethodsTo investigate the pathway of chloride retention in NS, we assessed the expression levels of both paracellular and transcellular components of chloride transport in the CD of POD-ATTAC mice and PAN rats, two rodent models of NS. We also used cultured mouse cortical collecting duct cells to see how overexpression or silencing of claudin-4 affect paracellular permeability. Finally, human renal biopsies were used to confirm our in vivo results. ResultsIn control animals, claudin-4 was expressed at low levels in collecting duct (CD). In POD-ATTAC mice and PAN rats, claudin-4 expression was strongly increased in CD beta-intercalated cells (B-IC) and to a lesser extent in CD principal cells and was also induced in connecting tubules. Similarly, we found that claudin-4 was expressed at low levels in normal human kidneys and was dramatically increased in CD cells of nephrotic human kidneys (focal and segmental glomerulosclerosis). In parallel, the expression of pendrin, which exchanges chloride for bicarbonates in B-IC, was decreased in nephrotic compared to control animals. However, the increase in claudin-4 expression observed in NS is likely independent of pendrin abundance. Increased claudin-4 abundance is coupled with increased ENaC-dependent sodium transport. Overexpression or silencing of claudin-4 in mCCDcl1 cells confirmed the preferential permeability of claudin-4 to chloride over sodium. ConclusionsThese results suggest that during NS, transcellular Cl-/HCO - transport decreases while paracellular chloride transport via claudin-4 may increase along the collecting system. Paracellular chloride permeability may constitute a chloride shunt that favors Na+ reabsorption and opposes K+ secretion along the CD in NS. Significance StatementNephrotic syndrome is a common disease characterized by massive proteinuria, hypoalbuminemia and edema due to renal sodium-chloride retention. We demonstrate for the first time an induction of claudin-4 expression indicating a partial shift from transcellular to paracellular chloride transport in the renal collecting system of nephrotic rodents. We confirmed the increased expression of claudin-4 in kidney biopsies of nephrotic patients, highlighting the translational significance of these results. Whether the paracellular pathway may represent a novel target to treat edema in nephrotic syndrome remains to be elucidated.

physiology↗

bioRxiv2022

Genetic load in incomplete lupus erythematosus

Incomplete lupus erythematosus (ILE) patients have lupus features but insufficient criteria for systemic lupus erythematosus (SLE) classification. Some ILE patients transition to SLE, but most avoid major organ involvement. This study tested whether the milder disease course in ILE is influenced by reduced SLE-risk allele genetic load. We calculated the genetic load based on 99 SLE-associated risk alleles in European American SLE patients (>4 ACR-1997 criteria, n=171), ILE patients (3 ACR-1997 criteria; n=174), a subset of ILE patients not meeting SLICC classification (ILESLICC, n=119), and healthy controls (n=133). ILE and SLE patients had significantly greater SLE-risk allele genetic load compared to healthy controls, while ILESLICC patients had a trend toward an increased genetic load, although not statistically significant. However, the genetic load did not differ between ILE and SLE. In conclusion, ILE and SLE patients have comparable genetic loads of SLE risk loci, suggesting similar genetic predisposition between these conditions. Phenotypic differences between SLE and ILE may instead be influenced by ILE-specific variants and gene-environment interactions.

immunology↗

bioRxiv2018

The oxysterol synthesizing enzyme CH25H contributes to the development of intestinal fibrosis

Intestinal fibrosis and stenosis are common complications of Crohns disease (CD), frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidized cholesterol derivatives, with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase (CH25H) converts cholesterol to 25-hydroxycholesterol (25-HC), which modulates immune responses and oxidative stress. In human intestinal samples from CD patients we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme using the sodium dextran sulfate (DSS)-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

immunology↗