Progerin was present in arteries from 82 percent of patients with chronic kidney disease – averaging 0.1 percent to 8.1 percent of vascular smooth muscle cells across sections, with peaks up to 21 percent in a single section – and was more frequent in calcified vessels and with longer disease duration, according to new research.
The study, published in Nature Aging, examined whether progerin and the LMNA c.1824C>T variant occur as somatic events in arteries from patients with stage 5 chronic kidney disease (CKD) and whether these molecular features align with early vascular aging.
Epigastric arteries from 50 patients undergoing living-donor renal transplantation and 34 controls were assessed by immunostaining, RNA analysis, and droplet digital polymerase chain reaction.
The Hutchinson–Gilford progeria syndrome mutation LMNA c.1824C>T was detected as a somatic variant in 78 percent of CKD arteries.
Progerin-positive cells appeared as scattered cells and as adjacent clusters. Progerin frequency was higher in calcified than noncalcified arteries and correlated with the number of years since CKD diagnosis. The variant was also present at low allele fractions in peripheral blood mononuclear cells from patients and from control participants.
In mosaic induced pluripotent stem cell-derived vascular smooth muscle cells (VSMCs), uremic serum increased endoplasmic reticulum (ER) stress in both progerin-negative and progerin-positive cells, with progerin-positive cells showing higher baseline ER stress yet maintaining proliferation comparable to controls, as assessed by PCNA staining.
In vivo lineage tracing in Myh11:Confetti mice carrying the murine Lmna 1827C>T allele showed that progerin-expressing VSMCs tended to form larger single-color clones during postnatal growth.
In adult mice with mosaic VSMC progerin expression, arterial findings included higher ER stress, reduced VSMC density, increased medial fibrosis, and increased expression of osteogenic markers runt-related transcription factor 2 and secreted phosphoprotein 1.
In patient arteries, progerin-positive cells correlated with DNA damage by p53-binding protein 1 and with senescence markers p21 and p16. Together, the human tissue, cell, and mouse data described clonal occurrence of LMNA c.1824C>T with recurrent progerin expression and associations with ER stress, DNA damage, senescence, and histologic features consistent with early vascular aging in CKD.
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