Background and objectivesElevated fibroblast growth factor-23 (FGF23) has been consistently associated with heart failure, particularly heart failure with preserved ejection fraction, among patients with CKD and in the general population. FGF23 may directly induce cardiac remodeling and heart failure. However, biases affecting observational studies impede robust causal inferences. Mendelian randomization leverages genetic determinants of a risk factor to examine causality. We performed a two-sample Mendelian randomization to assess causal associations between FGF23 and heart failure.Design, setting, participants, & measurementsGenetic instruments were genome-wide significant genetic variants associated with FGF23, including variants near PIP5K1B, RGS14, LINC01229, and CYP24A1. We analyzed data from the Heart Failure Molecular Epidemiology for Therapeutic Targets and BioVU biobanks to examine associations of the four variants with overall heart failure, heart failure with preserved ejection fraction, and heart failure with reduced and mid-range ejection fraction. We developed an eGFR polygenic risk score using summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) genome-wide association study of eGFR in >1 million individuals and performed stratified analyses across eGFR polygenic risk score strata.ResultsGenetically determined FGF23 was not associated with overall heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium (odds ratio, 1.13; 95% confidence interval, 0.89 to 1.42 per unit higher genetically predicted log FGF23) and the full BioVU sample (odds ratio, 1.32; 95% confidence interval, 0.95 to 1.84). In stratified analyses in BioVU, higher FGF23 was associated with overall heart failure (odds ratio, 3.09; 95% confidence interval, 1.38 to 6.91) among individuals with low eGFR-polygenic risk score (<1 SD below the mean), but not those with high eGFR-polygenic risk score (P interaction = 0.02). Higher FGF23 was also associated with heart failure with preserved ejection fraction among all BioVU participants (odds ratio, 1.47; 95% confidence interval, 1.01 to 2.14) and individuals with low eGFR-polygenic risk score (odds ratio, 7.20; 95% confidence interval, 2.80 to 18.49), but not those high eGFR-polygenic risk score (P interaction = 2.25 × 10−4). No significant associations were observed with heart failure with reduced and midrange ejection fraction.ConclusionWe found no association between genetically predicted FGF23 and heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium. In BioVU, genetically elevated FGF23 was associated with higher heart failure risk, specifically heart failure with preserved ejection fraction, particularly among individuals with low genetically predicted eGFR.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_07_28_CJN00960122.mp3
and genome-wide association studies identified dachshund homolog 1 (DACH1), which suppresses tubular cell cycle progression, as having protective effects on CKD (7). Though suggestive that ongoing tubular cell cycling may be detrimental, few studies have directly manipulated cell cycle progression in the chronically injured kidney to determine how tubular cell cycle alters tubular injury and fibrosis.Most proximal tubules in the uninjured kidney are quiescent (G0) but, upon injury, reenter the cell cycle at G1, which is the first cell cycle checkpoint. Actively cycling cells progress from G1/S phase (DNA synthesis); then to the second checkpoint, G2; and finally to M (mitosis). Work has established that some tubule cells arrest at G2/M following injury, and these G2-arrested cells play an important role in CKD progression through production of profibrotic growth factors like TGF-β and CTGF (8). However, little is known about the role of cell cycle progression at the G1/S transition in chronically injured tubules. Cyclin dependent kinases 4 and 6 (CDK4/6) combine with cyclin D1 to phosphorylate retinoblastoma protein (Rb), leading to the liberation of E2F, a transcription factor that promotes expression of genes related to G1/S phase progression. The FDA-approved drug palbociclib is a highly selective inhibitor of CDK4/6 that is currently used to treat patients with breast cancer and provides an important tool to assess how G1/S cell cycle progression alters CKD progression.In this manuscript, we use a cell cycle reporter mouse to confirm that cell cycle is persistently altered in the chronically injured proximal tubules. Blocking CDK4/6 in mice after 2 different models of CKD significantly reduced tubular cell cycle progression, ameliorated tubular injury, preserved renal function, and decreased tubulointerstitial fibrosis. Surprisingly, selective tubular deletion of cyclin D1 worsened, rather than improved, tubular injury in murine CKD. Human expression quantitative trait loci (eQTLs) and genome-wide association study (GWAS) data are consistent with the murine studies showing that inhibiting CDK4/6, but not cyclin D1, protects against CKD. Mechanistically, CDK4/6 inhibition reduced proximal tubule cell death through a pathway involving STAT3/IL-1β.
Floodplain reconnection projects are largely nature-based solutions that have great potential to restore channel stability, attenuate stormwater, improve flood resilience, and improve water quality. The suite of possible restoration options for a given study area must consider the multiple uses and functions of river corridors, along with the potential impacts and benefits to adjacent infrastructure. Therefore, decision-support frameworks designed to help stakeholders compare floodplain reconnection scenarios to best meet site-specific design objectives are needed. A River Scenario Evaluation Tool (RiverSET) was designed in Python as a wrapper around a two-dimensional hydraulic model (2D Hydrologic Engineering Center's River Analysis System, 2D HEC-RAS) to guide an alternative analysis of various floodplain reconnection techniques. RiverSET runs each reconnection scenario in sequence and extracts the values needed to evaluate scenarios at user-defined regions of interest. The results of these evaluation parameters (depth, duration, stream power, percent time inundated, and velocity) are compiled and displayed for review and synthesis. RiverSET's utility is demonstrated here through a case study on the Black Creek in Vermont, United States, involving five floodplain reconnection scenarios and a variety of stakeholders.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.