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The role of Gucy1α1-positive fibroblasts in maladaptive renocardiac crosstalk and fibrosis

Award Number: F32HL189102
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/10/2027
PERIOD OF PERFORMANCE END DATE: 03/09/2028

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The role of Gucy1α1-positive fibroblasts in maladaptive renocardiac crosstalk and fibrosis - PROJECT SUMMARY Multiorgan crosstalk is an essential component of cardiorenal syndrome (CRS), a debilitating condition whereby primary fibrotic kidney injury causes excessive myocardial extracellular matrix (ECM) deposition, thus promoting heart failure (HF). Despite HF prevalence reaching 39.1% in advanced chronic kidney disease (CKD), mechanistic understanding of renocardiac crosstalk has not yet been achieved. Kidney fibroblasts are key CKD effectors, yet their direct role in secondary cardiac impairment in CRS has not been studied. Lack of specificity among currently used fibroblast markers averts such crucial research. Our recent single-cell RNA-sequencing (scRNA-seq) revealed that Gucy1α1 which encodes an alpha subunit of soluble guanylate cyclase 1 (SG-1) exclusively marks fibroblasts in the normal kidney and at multiple stages of acute kidney injury (AKI) to CKD progression in two independent models. Genetic lineage tracing in our new Gucy1α1CreERt2;eGFP (G-eGFP) reporter mice revealed Gucy1α1-driven eGFP expression restricted to resident fibroblasts in the normal kidney with no unspecific podocyte, endothelial, epithelial or immune labeling. After injury, renal eGFP+ populations significantly expanded and acquired alpha smooth muscle actin (αSma) expression indicative of activated myofibroblast (MF) phenotype. Thus, our proposal employs a novel tool which offers selectivity advantage in kidney fibroblast targeting. We then used it to examine the functional role of Gucy1α1+ fibroblasts in the renal unilateral ischemia-reperfusion (UIR) model, since we and others have previously shown that it mimics renocardiac remodeling and crosstalk observed in CRS. Of note, diphtheria toxin A (DTA) mediated ablation of Gucy1α1+ cells resulted in significantly exacerbated renal parenchymal damage and fibrosis following UIR. Moreover, Gucy1α1+ fibroblasts ablation augmented secondary cardiac hypertrophy and fibrosis caused by primary renal UIR. These preliminary findings suggest that Gucy1α1+ fibroblasts are pivotal for renocardiac remodeling and crosstalk, yet the underlying mechanisms remain elusive. We recently found that kidney injury triggers elevated cell-to-cell interactions driven by Gucy1α1+ activated fibroblasts which upregulate Col18α1. Previous studies showed that Col18α1 C-terminal fragment endostatin alleviates pathologic renal and cardiac remodeling and dysfunction. We found that UIR triggers plasma and renal Col18α1-endostatin upregulation. Remarkably, Gucy1α1+ fibroblasts ablation reverses that effect to the baseline levels. Thus, we hypothesize that Gucy1α1+ kidney fibroblasts mediate renocardiac fibrotic remodeling and HF via Col18α1 signaling. Aim 1 will examine direct and indirect effects of Gucy1α1+ fibroblasts on renocardiac crosstalk. Using DTA-mediated approach, we will delete Gucy1α1+ populations before and after primary kidney injury and evaluate cardiorenal parameters. To separate the secretory fibroblast ablation effects from general effects of kidney injury, we will attach WT mice to the Gucy1α1+ ablated mice via parabiosis. Aim 2 will evaluate the role of Col18α1-endostatin in renocardiac interactions in vitro and in the settings of in vivo Gucy1α1+ fibroblasts ablation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $84,148 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	1	9/11/2026	NEW	$84,148
														Subtotal = $84,148

Grand Total All Awards = $84,148

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The role of Gucy1α1-positive fibroblasts in maladaptive renocardiac crosstalk and fibrosis

Award Number: F32HL189102

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/10/2027

PERIOD OF PERFORMANCE END DATE: 03/09/2028

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