The secretory peptidase inhibitor R3HDML fine-tunes p38 MAPK signaling to maintain glomerular basement membrane architecture during renal aging and disease
Year: 2026
Type: article
Abstract: Serine proteases and their inhibitors are the most abundant class of proteolytic enzymes, involved in numerous biological processes such as cellular crosstalk. However, their role in renal diseases remains controversial. In this study, we identified the putative serine peptidase inhibitor R3HDML as a podocyte-specific expressed and secreted protein. CRISPR/Cas9-mediated generation of a novel floxed- R3hdml allele, demonstrated a regulatory function in renal aging and diabetic nephropathy. R3hdml knockout mice developed hump-like collagen IV deposits in the glomerular basement membrane (GBM), as well as mesangial expansion. These deposits induced the retraction of podocyte protrusions and the formation of a clustered, synaptopodin-positive actin cytoskeleton via integrin adhesion signaling. Despite the development of these key podocytopathy features, renal function was not severely impaired by the loss of R3hdml in aging, diabetic nephropathy, and during ischemia-reperfusion induced tubular injury and regeneration. Interaction proteomics revealed p38 MAPK signaling-related kinases, collagen modifiers, and N-terminal signaling peptide containing proteins, as potential R3HDML interactors. Consequently, Thr180/Tyr182 phosphorylation of p38 MAPK and downstream collagen IV deposition were suppressed by R3HDML in podocytes. In summary, we demonstrate a cell type specific mechanism by which podocytes maintain the composition and structure of the GBM in ageing and disease.
Source: Scientific Reports
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
Awards: G1078610655, G1408341393, G1501190094, G1605809255, G1733652078, G1864158113, Verbund SATURN3 - Räumliche und zeitliche Auflösung der intratumoralen Heterogenität bei den drei schwer zu behandelnden Krebsarten Brustkrebs, Darmkrebs und Bauchspeicheldrüsenkrebs, Standort Universität Köln, GRK 2344: MeInBio BioInMe: Untersuchung räumlicher und zeitlicher Dynamik der Genregulation mit hochauflösenden Hochdurchsatzverfahren, G2129958476, G2605962356, FOR 5476: UcarE Urothelkarzinom Epigenetik, G2734540422, G2837854789, G2899880, Morphofunktionelle Dekodierung von ZellMatrix Interaktionen in nephropathologischen und uropathologischen Erkrankungen, PM4Onco - Medizininformatik-Use Case 'Personalisierte Medizin für die Onkologie' - Teilvorhaben: Koordination, Integration Krebsregisterdaten, Patient Journey, Kerndatensätze, Bioinformatik-/Dateninfrastrukturen, Erweiterte Analytik und Roll-Out: UK Freiburg, G3562415423, SFB 1479: Onkogengetriebener Immun Escape (OncoEscape), SFB 1453: Nephrogenetik (NephGen), SFB 1160: Immunpathologie aufgrund eingeschränkter Immunreaktionen (IMPATH), G4854266585, STOP-FSGS - Translationaler Forschungsverbund zur Verbesserung der Diagnostik und Therapie der FSGS, TP 3: Targeting von Signalwegen, TP 6: Entschlüsselung und Stratifizierung der humanen FSGS, G5224721593, G5451248522, G561423854, G5695602447, Modulation des Podozytären Aktinzytoskeletts, G5843413618, G6000535164, G600451091, G6412650905, G6925941660, G6952166915, G699314248, G7399536025, ZellMatrix Interaktionen renaler tubulärer Epithelien: Implikationen des kortikalen Aktinzytoskeletts und der tubulären Basalmembran, G7711711598, G7792490946, G7893660435, G8252797746, G8314964729, G8535061057, G855946224, TRR 353: Regulation von Entscheidungen in Zelltodprozessen, G982794282
OpenAlex ID: W7223560291