Chade, Alejandro R

Cardiovascular-kidney-metabolic (CKM) syndrome is a complex disease that affects up to 90% of US adults. This work characterized the renal transcriptomic landscape of a novel model of CKM in aging swine. The cardiovascular, renal, and metabolic parameters in pigs are very similar to those in humans, and our work may guide future studies aimed at modulating specific age-related renal abnormalities in CKM to slow disease progression and reduce mortality.

Key Points We characterized the renal transcriptional profile at the single-nuclear level in a preclinical swine model of CKD. Our study reveals that renal endothelial cells represent the cluster with the highest number of differentially expressed genes related to inflammatory and fibrotic activity. These results offer new insights into CKD-induced transcriptional changes in renal endothelial cells at the single-nuclear level. Background The prevalence of CKD is on the rise, and precision strategies to offset the progression to ESKD are needed. We used a well-established preclinical translational model of CKD in swine and single-nucleus RNA sequencing (snRNA-seq) to identify potential therapeutic targets through characterization of the renal cell-specific transcriptomic landscape. Methods Normal and CKD pigs were studied in vivo and ex vivo after 14 weeks ( n =6/group). In randomly selected pigs ( n =3/group), kidneys were harvested, nuclei isolated, libraries prepared, and snRNA-seq performed. Protein expression of candidate differentially expressed genes (DEGs, log2FC >0.25, adjusted P value < 0.05) was determined by immunohistochemistry, and their expression in primary normal and CKD renal vascular endothelial cells was modulated (small interfering RNA) in vitro . Results A total of 52,213 nuclei were analyzed. Thirty clusters were identified and filtered by canonical gene markers, revealing 16 unique renal cell types. Endothelial cells were the top cell type exhibiting the highest number of DEGs, which were subsequently filtered by angiogenesis, inflammation, and fibrosis (major injurious pathways altered in CKD kidneys). Venn diagram analysis identified five unique overlapping DEGs in endothelial cells: vWF , LAMA3 , and KDR upregulated and PTGIS and ICAM1 downregulated in CKD versus normal kidneys. Venn diagram analysis indicates that vWF , LAMA3 , and ICAM1 participate in inflammatory and fibrotic signaling. Renal protein expression of these DEGs matched snRNA-seq findings. Furthermore, in vitro silencing of vWF and LAMA3 ameliorated endothelial cell inflammatory and fibrotic signaling. Conclusions Our work characterized the single-nuclear renal cell transcriptomic landscape of a translational model of CKD and singled out genes implicated in major renal injury pathways. These genes could serve as potential targets to pave the way for new therapeutic strategies in patients with CKD.

Almost a hundred years have passed since obstruction of the renal artery has been recognized to raise blood pressure. By now chronic renovascular disease (RVD) due to renal artery stenosis is recognized as a major source of renovascular hypertension and renal disease. In some patients, RVD unaccompanied by noteworthy renal dysfunction or blood pressure elevation may be incidentally identified during peripheral angiography. Nevertheless, in others, RVD might present as a progressive disease associated with diffuse atherosclerosis, leading to loss of renal function, renovascular hypertension, hemodynamic compromise, and a magnified risk for cardiovascular morbidity and mortality. Atherosclerotic RVD leads to renal atrophy, inflammation, and hypoxia but represents a potentially treatable cause of chronic renal failure because until severe fibrosis sets in the ischemic kidney, it retains a robust potential for vascular and tubular regeneration. This remarkable recovery capacity of the kidney begs for early diagnosis and treatment. However, accumulating evidence from both animal studies and randomized clinical trials has convincingly established the inadequate efficacy of renal artery revascularization to fully restore renal function or blood pressure control and has illuminated the potential of therapies targeted to the ischemic renal parenchyma to instigate renal regeneration. Some of the injurious mechanisms identified as potential therapeutic targets included oxidative stress, microvascular disease, inflammation, mitochondrial injury, and cellular senescence. This review recapitulates the intrinsic mechanisms that orchestrate renal damage and recovery in RVD and can be harnessed to introduce remedial opportunities.

Chronic kidney disease (CKD) often leads to left ventricular diastolic dysfunction (LVDD) and heart failure. Using a novel translational swine model of CKD-LVDD, we characterize the cardiac epigenetic landscape, identifying site-specific 5-methylcytosine changes in vascular endothelial growth factor (VEGF)-related genes associated with impaired angiogenesis and cardiac microvascular rarefaction. These observations shed light on the mechanisms of cardiac microvascular damage in CKD-LVDD and may assist in developing novel therapies for these patients.

Chronic kidney disease (CKD) is a progressive disorder in which more than 50% of deaths are attributed to cardiovascular disease. Using a swine model of CKD that develops left ventricular dysfunction (CKD-LVDD), we characterize the cardiac micro-RNA and transcriptomic profile, identifying dysregulated genes associated with cardiac remodeling and fatty acid metabolism that might be post-transcriptionally regulated early in the disease. These findings pinpointed pathological pathways that may open new avenues toward therapeutic research to reduce cardiovascular morbidity in CKD.

Chronic kidney disease (CKD) is a progressive disorder with high cardiovascular morbidity and mortality. This work supports the role of inflammatory cytokines of renal origin in renal-cardio pathophysiology in CKD and that the heart may be a target. Furthermore, it supports the feasibility of a new strategy in a translational fashion, using targeted inhibition of renal NF-κB signaling to offset the development of cardiac injury in CKD.