Role of Recurrent Somatic Mutation and Progerin Expression in Early Vascular Aging of Chronic Kidney Disease

Geriatrics Basic Medical Sciences Nephrology Cell Biology Biochemistry Genetics Cardiovascular System Life Sciences Medicine
chronic kidney disease vascular aging somatic mutations progerin vascular smooth muscle cells clonal expansion molecular mechanisms

1. Academic Background and Research Rationale

Chronic Kidney Disease (CKD) is a global public health challenge. Epidemiological data indicate that CKD affects approximately 10–12% of the world’s population, acting as a major driver of cardiovascular disease (CVD) mortality worldwide. CKD patients often display “Early Vascular Aging” (EVA) phenomena, including arterial wall thickening, a reduction in smooth muscle cells, and adventitial fibrosis, all of which substantially elevate the risk of cardiovascular and cerebrovascular events (such as myocardial infarction and stroke). Although clinically CKD is highly correlated with vascular aging, its molecular mechanisms and specific triggers have long remained unclear. The traditional view holds that oxidative stress and calcification in the uremic environment are the main drivers of EVA, but these explanations fail to fully account for the cardiovascular risk associated with CKD.

In the past decade, research on the relationship between somatic mutations and organismal aging and disease has gradually flourished. Studies of various organs—such as the esophagus, skin, and liver—have shown that humans continually accumulate random somatic mutations during development and aging, with some mutations even forming local clonal expansions and promoting disease. The development of new technologies (such as single-cell sequencing and digital PCR) has enabled researchers to track minute somatic mutations and cellular clonal dynamics. However, the functional role of local vascular wall mutations in CKD-related EVA, whether they can lead to vascular dysfunction, and their association with classic aging or hereditary mutations (such as progeroid syndromes), are still unknown.

A particularly intriguing clue has come from a rare mutation-driven progeroid disease—Hutchinson–Gilford Progeria Syndrome (HGPS)—which is caused by a specific heterozygous c.1824C>T mutation in the LMNA gene. This mutation leads to abnormal splicing and the production of a harmful protein called “progerin,” resulting in accelerated systemic aging in children, especially manifesting as vascular lesions and a high incidence of cardiovascular events. Although progerin expression has occasionally been observed in the arteries of healthy individuals, the frequency is extremely low (0.001%-0.09%) and its pathogenic significance remains unclarified.

Based on this, the research team proposed a logical hypothesis: In the vascular wall exposed to CKD, could there exist driver somatic mutations—such as the progeroid mutation of LMNA? Could these mutations undergo clonal expansion in vascular smooth muscle cells (VSMCs) and promote local vascular aging? If so, this would imply that under certain pathological stresses, human tissues could “repurpose” known pathogenic gene pathways (such as progeroid mechanisms), thus establishing new driving forces for vascular aging.

2. Authors and Source of the Paper

This study was conducted by a multinational academic team led by Gwladys Revêchon, Anna Witasp, Nikenza Viceconte, and others. The main author affiliations include world-renowned medical research institutions such as Karolinska Institutet (Sweden), University of Glasgow (UK), Duke University (USA), and RWTH Aachen University (Germany). The work was published in the authoritative international journal Nature Aging (Nature Aging | volume 5 | June 2025 | 1046–1062), DOI: https://doi.org/10.1038/s43587-025-00882-6.

3. Overall Study Design and Technical Methods

1. Research Subjects and Sample Preparation

This study focused on the molecular mechanisms of early vascular aging in CKD, conducting a series of experiments. The main research groups included:

  • CKD Group: 50 CKD stage 5 patients (glomerular filtration rate <15ml/min) whose infra-epigastric artery specimens were collected during living-donor renal transplantation.
  • Control Group: 34 non-CKD individuals divided into two subgroups: 24 without a history of CVD as healthy controls, and 10 with a history of CVD as CVD controls. Peripheral blood mononuclear cells (PBMCs) were also collected from some subjects.

All tissue samples were formalin-fixed and paraffin-embedded (FFPE) for subsequent molecular and histological analyses.

2. Detection and Localization of Progerin Expression

The core of the study was to explore progerin distribution and expression levels in vascular wall VSMCs. The team used a specific antibody combined with immunofluorescence to stain arteries from CKD and control groups for progerin protein, together with αSMA (VSMC marker) and CD31 (endothelial marker) for multi-target spatial localization. Microscopy combined with automated software-based nuclear counting was used to accurately determine the proportion and spatial distribution (either solitary or clustered) of positive cells.

3. Detection of LMNA c.1824C>T Mutation and Clonal Analysis

To investigate the source of progerin expression, the researchers used droplet digital PCR (ddPCR) to directly detect the presence and frequency (fractional abundance, FA) of the LMNA c.1824C>T (human progeria mutation) in the arterial wall DNA. They also tested this mutation’s low-frequency presence in PBMCs. Additionally, mutations in other known disease genes (such as CFTR, EGFR, DMD, LAMA2) were assessed to substantiate the prevalence and hotspot nature of somatic mutations.

4. Pathological and Cellular Function Analysis

Arteries from CKD patients were further divided into calcified and non-calcified categories. The team used TUNEL staining, cell layer counts, and immunostaining to detect apoptosis and proliferation (Ki67/PCNA), cellular senescence (p16/p21/p53), ER stress (BIP), and DNA damage (53BP1/ATR) markers. By statistically analyzing their correlation with the proportion of progerin-positive cells, the biological effects of progerin expression were inferred.

5. In Vitro Cell Experiments and Uremic Environment Simulation

To simulate the effects of the CKD-related “uremic environment” on cellular proliferation and biological responses, the researchers used human iPSC-derived VSMCs to establish a 10% HGPS and 90% normal cell mixed “mosaic” culture system, which was treated either with uremic serum from CKD patients or healthy serum. The survival, ER stress, and growth of progerin-positive cells were then assessed.

6. In Vivo Mouse Lineage Tracing and Functional Validation

A triple transgenic mouse model (Myh11-CreERT2/Lmna^1827T/Confetti; mimicking the human HGPS mutation) was used. Tamoxifen was applied to induce limited progerin expression and multicolor fluorescent labeling in VSMCs, enabling tracking of the clonal expansion capacity and functional impact of progerin-positive cells during mouse arterial growth and repair (with analyses covering postnatal, adult, and post-injury/10-week stages). Pathological analyses were performed in parallel to assess vascular aging phenotypes.

4. Analysis of Main Results

1. Progerin Expression in CKD Vessels and Its Characteristics

Experimental data showed that progerin expression was detectable in the infra-epigastric arteries of 82% of CKD patients, with nuclear localization in VSMCs. Both solitary and clustered (cell group) distributions were observed. The highest single-section positivity reached 21.1%; multi-section averages ranged from 0.1–8.1%, significantly higher than the control group (<0.1%). Meanwhile, progerin mRNA was only detectable in CKD arteries but not in controls. There was no correlation between age and progerin expression, indicating that the CKD environment is the determining factor.

2. Discovery and Characterization of LMNA c.1824C>T Somatic Mutation

A key finding was that the LMNA c.1824C>T mutation was detected by ddPCR in 78.3% of CKD arteries, with a mean FA of 11.32% (controls 0.43%; CVD controls 0.07%). The mutation corresponded spatially with progerin-positive regions, indicating that this somatic mutation is the main source of progerin expression. This alteration was detected in PBMCs at extremely low FA (<0.06%) in both CKD and healthy elderly, suggesting the locus is a mutational hotspot for somatic events, but high-frequency presence is restricted to the local vessel wall.

3. Progerin Expression Correlates with Vascular Disease Progression

Arterial calcification, VSMC loss, and decreased cell density are common in CKD patients, and the proportion of clustered progerin-positive cells is significantly correlated with calcification severity. In addition, progerin expression is positively associated with CKD disease duration and degree of calcification, pointing to its key role in vascular disease progression.

4. Clonal Expansion and Biological Effects of Progerin-Positive Cells

Immunohistochemistry and spatial imaging analysis showed that about 40.1% of progerin-positive VSMCs are distributed in clusters, highly consistent with LMNA mutation FA. Theoretical calculations indicate the probability of adjacent positive cells arising by chance is extremely low, evidencing significant clonal expansion. Proliferation markers (Ki67, PCNA) revealed that progerin-positive cells have similar proliferative potential as progerin-negative cells, with those in clusters more likely to express proliferation markers, suggesting a growth advantage during local vascular injury repair.

5. In Vitro and In Vivo Experiments: Behavior of Progerin Cells in Uremic Environment

In vitro mosaic culture and uremic serum intervention experiments showed that progerin+ VSMCs were not reduced in distribution or survival under uremic conditions, and although ER stress increased, they maintained proliferation capabilities comparable or superior to normal cells. Mouse lineage tracing demonstrated that in the process of vascular injury repair and growth in Lmna^1827T mutant mice, progerin+ VSMCs underwent effective clonal expansion, forming larger cell groups (clusters) than wild-type, but accumulated progerin led to increased ER stress, DNA damage, and higher senescence markers, inducing vascular tissue aging phenotypes (decline in VSMC number, collagen deposition, upregulation of osteogenic genes).

6. Molecular Pathological Mechanism Analysis

Regardless of in vitro or in vivo, in both CKD patient and mouse samples, progerin-positive cells showed significant ER stress (BIP+), DNA damage (53BP1/ATR+), and cellular senescence (p16/p21 upregulation). Notably, DNA damage and senescence markers were far higher in progerin+ than in negative cells, indicating that somatic mutation-induced progerin has a direct pathogenic effect on local cells, promoting early exhaustion of the vascular microenvironment and structural/functional impairment.

5. Conclusions, Significance, and Research Highlights

This study systematically reveals a novel molecular mechanism underlying CKD-associated early vascular aging: progerin expression and clonal expansion driven by somatic LMNA mutations. The evidence chain comprehensively links progerin production → clonal expansion → ER stress/DNA damage → cellular senescence → vascular early aging in a pathogenic cascade. This finding:

  1. Pioneeringly and for the first time confirms that in non-hereditary progeria patients, local tissues (CKD blood vessels) can spontaneously acquire “progeria-type” somatic mutations, which clonally expand under chronic injury environments—becoming a new mechanism for metabolically related organ aging.
  2. Improves the theoretical model of “somatic mutation–organ aging”, providing a theoretical basis for identifying high-risk populations for vascular aging diseases, evaluating individualized cardiovascular risks, and developing new molecular targets.
  3. Methodologically innovative by leveraging state-of-the-art ddPCR, lineage tracing, and multi-marker immunostaining to achieve high-resolution analysis of ultra-low-frequency mutations and their functional effects.
  4. Has both clinical and fundamental value, indicating that traditional CVD risk prediction should pay attention to tissue-level mutation-driven events, and providing molecular evidence for early screening, warning, precision treatment, and rehabilitation interventions in CKD with vascular complications.
  5. Offers a new perspective reference for tissue aging in other chronic diseases: Conditions such as diabetic nephropathy and chronic inflammatory organ diseases could also adopt the “somatic clonal mutation” and progeroid mechanism, opening up new target development space for the microenvironment and local cell populations.

6. Additional Valuable Information

  • This study for the first time applies the hereditary accelerated aging pathway of HGPS to the somatic mutational field in chronic degenerative lesions, connecting the research areas of genetic disease, somatic clones, chronic disease, and organ aging.
  • The comprehensive somatic mutation analysis across multiple genes and disease loci prepares the technical foundation for future studies exploring non-traditional hereditary backgrounds and cumulative effects in chronic organ aging, enabling more holistic risk prediction.
  • The authors propose that “high mutational hotspots + chronic stress + local expansion” may constitute a common pathogenic pathway in organ aging across diverse chronic diseases, providing new avenues for precision medicine and cellular/genetic therapies.
  • The paper highlights the necessity for close integration of clinical and basic research, urging a break from traditional risk mindsets and bold exploration of tissue-specific and spatiotemporal molecular abnormalities.

7. Summary

This original research published in Nature Aging, through multi-center clinical samples and innovative in vitro and in vivo methodologies, systematically elucidates the molecular underpinnings of early vascular aging induced by CKD. The article proposes a new paradigm of “somatic mutation → clonal expansion → local progeroid changes → organ dysfunction,” providing a robust foundation and rich imaginative scope for future molecular mechanism studies, individualized risk stratification, and targeted therapy of chronic degenerative diseases.