As FGGS developed, podocyte depletion, cellular senescence markers, and PEC activation were associated with tuft contraction and increased with hypertension.
Key Findings
Results
The frequency of tuft contraction and global glomerulosclerosis was significantly greater in hypertensive kidneys compared to non-hypertensive kidneys.
Kidney tissue from 26 hypertensive and 25 age-matched non-hypertensive patients was analyzed.
The frequency of tuft contraction (TC) was greater in hypertensive kidneys (p < 0.01).
The frequency of global glomerulosclerosis (GGS) was greater in hypertensive kidneys (p < 0.001).
Glomerular expression of senescence markers was correspondingly higher in hypertensive kidneys.
Results
Podocyte numbers decreased in association with tuft contraction during focal global glomerulosclerosis development.
Podocyte number was quantified using a WT1 antibody via immunohistochemistry.
With tuft contraction (TC), podocyte numbers decreased.
Podocyte depletion was associated with TC and increased with hypertension.
WT1-expressing parietal epithelial cells (PECs) increased with TC.
Results
Senescence-related biomarkers p16, p21, β-galactosidase (GLB1), and CD73 were upregulated in glomeruli undergoing tuft contraction.
Immunohistochemistry (IHC) was employed to detect p16, p21, GLB1, and 5-nucleotidase (CD73).
With TC, increased glomerular p16, p21, GLB1, and CD73 expression was observed.
TC and GGS expressed senescent markers in both hypertensive and non-hypertensive kidneys.
Glomerular expression of senescence markers was higher in hypertensive kidneys corresponding to greater TC and GGS frequency.
Results
Parietal epithelial cell activation, marked by CK7 and CD44 expression, increased with tuft contraction during FGGS development.
Antibodies against annexin 3 (ANXA3), cytokeratin 7 (CK7), and CD44 were used to evaluate parietal epithelial cell (PEC) activation.
With TC, CK7 and CD44-expressing PECs increased.
PEC activation was associated with TC and increased with hypertension.
WT1-expressing PECs also increased with TC.
Results
Greater p16 and p21 expression was observed in the tubular atrophy associated with hypertension.
p16 and p21 are established biomarkers for cellular senescence.
Tubular atrophy in hypertensive kidneys showed greater expression of both p16 and p21 compared to non-hypertensive kidneys.
This finding extended the association of senescence markers beyond glomeruli to the tubulointerstitial compartment in hypertension.
Background
Arterionephrosclerosis is characterized by focal global glomerulosclerosis (FGGS), which begins as normal-appearing glomeruli that undergo tuft contraction and progress to global glomerulosclerosis.
FGGS is described as a constant feature of aging and hypertension.
The progression sequence is: normal-appearing glomeruli → tuft contraction (TC) → global glomerulosclerosis (GGS).
The relationships between biomarkers, hypertension, TC, and GGS were quantitatively analyzed.
Glomerular volume was analyzed alongside podocyte number and senescence biomarkers.
Hughson M, Ali A, Okabayashi Y, Puelles V, Bertram J. (2026). Hypertension and age-related focal global glomerulosclerosis are associated with biomarkers for cellular senescence.. Physiological reports. https://doi.org/10.14814/phy2.70730