Mrug, M. | bioRxiv Science

bioRxiv2026

Unmasking Early Renal Fibrosis in Polycystic Kidney Disease Using Noninvasive Precision Molecular MRI of Collagen

Fibrotic remodeling of extracellular matrix is a central driver of autosomal dominant polycystic kidney disease (ADPKD) progression since early stages of the disease. Unfortunately, it cannot be assessed with currently available methodologies before irreversible structural and functional decline, creating a diagnostic blind spot that hinders accurate early risk stratification and management. Here, we report the development of Gd-hProCA32.Collagen, a collagen -targeted protein MRI contrast agent that enables precision molecular MRI (pMRI) of early fibrosis by directly imaging collagen type I deposition in vivo before conventional laboratory and imaging methods detect changes in kidneys and liver of Pkhd1PCK/PCK (PCK) rats and Pkd2 mutant mice. Gd-hProCA32.Collagen, used at 10-fold lower dose, outperformed the widely clinically used agent gadobutrol (Gadovist), detecting approximately 2.8-fold greater total renal cyst volume ([~]8,500 vs [~]3,000 mm3, p<0.0001) and 1.5-fold higher total cyst count ([~]245 vs [~]160, p<0.0001), with superior T1W and T2W kidney AUC (p<0.01 and p<0.001) and preferential sensitivity to small and medium cysts. Signal enhancement in kidneys and liver correlated strongly with histological collagen burden quantified by Sirius red staining, whereas Gadovist showed no meaningful correlation. Gd-hProCA32.Collagen also enabled in vivo visualization of previously undetectable changes resembling radial striations at sites of microcyst cluster-adjacent microfibrosis and sustained delayed MRI enhancement due to specific collagen binding. These results reveal a previously inaccessible subclinical fibrotic phase of cystic kidney and liver disease and establish collagen-targeted pMRI as a strategy for early noninvasive detection and spatial mapping of multi-organ extracellular matrix remodeling when conventional biomarkers remain non-discriminating. One-sentence summaryWe report a first-in-class collagen-targeted MRI contrast agent with Precision molecular MRI that noninvasively reveals a previously inaccessible subclinical fibrotic phase of polycystic kidney disease across kidney and liver, overcoming limitations of current diagnostic methodology.

molecular biology↗

bioRxiv2022

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse model gene expression reversion

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. With this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo. Collectively, these indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD. O_FIG O_LINKSMALLFIG WIDTH=110 HEIGHT=200 SRC="FIGDIR/small/518863v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@18af02org.highwire.dtl.DTLVardef@89d45corg.highwire.dtl.DTLVardef@d4fffdorg.highwire.dtl.DTLVardef@1f244b3_HPS_FORMAT_FIGEXP M_FIG Graphical abstract of the study created with Biorender.com. C_FIG

genomics↗