bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.09.09.750431

Prolactin Modulates Renal Ischemia Reperfusion Injury According to Sex and Cathepsin D Genotype

Verdugo, M. G.·Franco-Acevedo, A.·Ramos-Garcia, C. O.·Moreno-Carranza, B.·Adan-Castro, N.·Melo, Z.
View original source ↗Export metadata ↓

Abstract

Renal ischemia reperfusion injury (IRI) is a major driver of acute kidney injury and a critical determinant of long term renal outcomes. Although sex differences in susceptibility to renal injury are well recognized, the hormonal mechanisms underlying these disparities remain incompletely understood. Prolactin (PRL), a pleiotropic hormone, has been implicated in both protective and deleterious renal effects, while Cathepsin D (CTD), a lysosomal protease, cleaves PRL into Vasoinhibins that possess antiangiogenic and immunomodulatory properties. The impact of CTD deficiency on PRL's role in renal IRI has not been defined. Here, we investigated whether CTD regulated prolactin signaling modulates renal responses to IRI in a sex dependent manner. Wild type (WT) and heterozygous CTD mice of both sexes were subjected to unilateral renal IRI. PRL overexpression was achieved via lentiviral vector, and renal function, inflammatory cytokines, and angiogenic factors were assessed. In vitro Prolactin cleavage assays confirmed the enzymatic role of CTD. Proteomic analysis of renal cortex tissue was performed using label free LC MS/MS and pathway enrichment tools. CTD cleaved PRL into Vasoinhibins at physiological pH, an effect blocked by Pepstatin A. PRL effects varied by sex and genotype. In WT females, PRL reduced renal dysfunction and increased IL-6 and TGF beta; expression following IRI. CTD+/- females exhibited protection from injury, with PRL treatment reversing IL-6 induction. In males, PRL alone had modest effects, but CTD deficiency led to pronounced creatinine elevation, which PRL treatment normalized. Proteomic data revealed differential regulation of cytoskeletal and inflammatory proteins. Cathepsin D heterozygosity modifies PRL's biological effects on the injured kidney. The CTD, PRL axis regulates key inflammatory and angiogenic responses after IRI, revealing new mechanistic insights and potential therapeutic targets in acute kidney injury.

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Verdugo, M. G., Franco-Acevedo, A., Ramos-Garcia, C. O., Moreno-Carranza, B., Adan-Castro, N., Melo, Z.. 2026-09-15. Prolactin Modulates Renal Ischemia Reperfusion Injury According to Sex and Cathepsin D Genotype. https://doi.org/10.64898/2026.09.09.750431

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Thoracoabdominal pressure transmission during prone and supine cardiopulmonary resuscitation in fresh-frozen human cadavers

Background: Prone cardiopulmonary resuscitation (CPR) may be necessary when turning a prone patient supine would delay chest compressions. Although prone compressions can generate arterial pressures comparable with or greater than supine CPR, the pathway of pressure transmission is uncertain. We examined synchronized intrathoracic, intra-abdominal, and central arterial pressures in both supine and prone positions. Methods: Two thawed fresh-frozen adult cadavers underwent three, 2-minute mechanical CPR trials per position in a counterbalanced crossover sequence. Solid-state catheters recorded pleural, peritoneal, and central arterial pressures simultaneously. Trial-level outcomes included peak pressure, mean pressure, pressure-time area, and the mean peritoneal-to-pleural pressure gradient. Exploratory fixed-effects models included position, cadaver, and their interaction. Results: Prone CPR increased peak intrathoracic pressure by 7.04 mmHg, peak intra-abdominal pressure by 21.69 mmHg, and peak arterial pressure by 15.40 mmHg. Mean intra-abdominal and arterial pressures increased by 16.22 and 9.90 mmHg, respectively. The mean peritoneal-to-pleural gradient reversed direction from -8.46 mmHg supine to 4.85 mmHg prone. Intrathoracic pressure-time area increased 3.4-fold, from 1.62 to 5.46 mmHg{middle dot}s, and arterial pressure-time area increased 2.2-fold, from 2.96 to 6.42 mmHg{middle dot}s. Conclusions: Compared to supine, prone mechanical CPR generated higher arterial pressures and reversed the pressure relationship across the thoracoabdominal boundary in both cadavers. Higher abdominal pressure coincided with a larger intrathoracic pressure-time area, a pattern compatible with reduced caudal pressure dissipation.

physiology↗
bioRxiv2026

Genetic Variation, Iron Status, and FGF23 Signaling Converge to Regulate Renal Calcium Buffering in Sickle Cell Disease

Sickle cell disease (SCD) causes heterogeneous mineral imbalances including variable degrees of hypocalcemia. The kidney controls systemic calcium by reabsorbing calcium from the glomerular filtrate via paracellular transport and transcellular transport in the nephron tubules, yet it is unknown whether these processes are modulated by genetic or environmental factors or disrupted in SCD. Using SCD mouse models and single-cell multiomics, we identify the distal convoluted tubule (DCT) as the nephron segment most susceptible to calcium reabsorption dysfunction in SCD, mainly via reduction of calcium buffer protein calbindin 1 (CALB1). We show that CALB1 and its encoding mRNA are decreased in DCT cells in SCD, alongside decreased Klotho (KL)-dependent fibroblast growth factor (FGF) 23 signaling and intracellular calcium signaling. Dietary iron restriction reduces CALB1, KL, and calcium exporter SLC8A1 levels in SCD kidneys. Loss of CALB1 shifts DCT cells toward energy-inefficient glycolysis with the metabolite 2,3-diphosphoglycerate impairing KL-dependent FGF23 signaling to create a feed-forward loop suppressing calcium reabsorption. Analysis of gene expression and protein quantitative trait loci data from kidneys of genetically diverse mice revealed that Calb1 expression levels are highly heritable and co-regulated with Slc8a1, identifying a genetic axis that dictates differential capacities for calcium buffering and trafficking toward blood in the kidney. Together, these findings support a model in which genetic variation, dietary iron status, and FGF23 signaling converge on DCT calcium buffering to reduce renal calcium reabsorption in the SCD kidney. This points to personalized, genotype- and iron-dependent strategies for managing mineral metabolism in SCD patients.

physiology↗
bioRxiv2026

Silver spoon effect: early-life environment and adult survival in a primate.

Early environmental conditions can have long-lasting effects on survival and reproductive fitness. Using a 23 year-long monitoring data set of captive mouse lemur's life history traits, we tested a relationship between maternal allocation to offspring (N = 1365) and their adulthood survival. Maternal characteristics such as age or body condition did not affect allocation to offspring whatever the litter size (1 to 3). Although birth mass depended on size and composition of the litters, mouse lemur survival was highly correlated with body mass acquired after weaning in both sexes, through potential sibling competition. Moreover, female's reproductive success correlated with this body mass and was consistently associated with increased longevity. These findings suggest the presence of a silver spoon effect under constant captive conditions. However, cumulative effects of genetic and adulthood social conditions strongly interact to affect adult survival. Deaths related to intra- or inter-sexes aggressive social interactions may outweigh effect of early environment and therefore minimize the silver-spoon effect on captive mouse lemur's survival. However, having a high body mass after weaning appeared to be a determinant factor in individual survival for mouse lemurs.

physiology↗