Cellular Senescence Is Associated with Faster Progression of Focal Segmental Glomerulosclerosis

Abstract

<b><i>Background:</i></b> A current, albeit unproven, hypothesis is that an acceleration of cellular senescence is involved in impaired renal repair and progression of glomerular diseases. Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a substantial risk for progression to ESRD. However, if and to what extent cell senescence predicts a negative outcome in FSGS is still unknown. <b><i>Methods:</i></b> The hypothesis that cell senescence represents a proximate mechanism by which the kidney is damaged in FSGS (NOS phenotype) was investigated in 26 consecutive kidney biopsies from adult FSGS cases (eGFR 72 ± 4 mL/min, proteinuria 2.3 ± 0.6 g/day) who were incident for 2 years in a Northern Italian nephrology center and had a 6-year clinical follow-up. <b><i>Results:</i></b> Cell senescence (p16<sup>INK4A</sup>, SA-β-galactosidase [SA-β-Gal]) was upregulated by ∼3- to 4-fold in both glomerular and tubular cells in kidney biopsies of FSGS as compared to age-matched controls (<i>p</i> < 0.05–0.01). Tubular SA-β-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16<sup>INK4A</sup> was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-β-Gal and p16<sup>INK4A</sup> were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16<sup>INK4A</sup> and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16<sup>INK4A</sup>, but not SA-β-Gal, contributed significantly to the prediction of eGFR loss. <b><i>Conclusions:</i></b> The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16<sup>INK4A</sup> in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS.

Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis

“…Although multiple cell types in the kidney can express markers of permanent cell cycle arrest, it is renal epithelial cell senescence that correlates most strongly to progressive fibrosis and functional loss in human biopsy samples (10,11). Increased senescent cell epithelial numbers are found in renal biopsies from older patients or those with kidney disease, and a greater epithelial senescent cell burden is associated with worse clinical outcomes in several renal conditions, including renal transplantation and glomerulonephritis (10,(12)(13)(14)(15)(16). Unlike with other cell types, epithelial cell senescence has been shown to accumulate with advancing age in murine models of aging and injury (9,17).…”

Sa-β-Gal in Kidney Tubules as a Predictor of Renal Outcome in Patients with Chronic Kidney Disease

“…This suggests that the aging phenotypes are differently expressed at the same time in the same tissue. In addition, the predictive role of SA-β-Gal on eGFR loss is still not known, since in studies obtained in small cohorts of patients with glomerular diseases, telomere shortening activity [16] and p16 INKA expression but not SA-β-Gal, were related to subsequent eGFR loss [17]. In this study, we tested the hypothesis that elevated SA-β-Gal activity in kidney biopsies is a predictor of subsequent eGFR loss in patients with CKD.…”

Dual-Signal Triple-Mode Optical Sensing Platform for Assisting in the Diagnosis of Kidney Disorders

“…Finding correlations between NAG and other biomarkers can help for further differentiation and follow-up inspection of diseases . Senescence-associated β-GAL has been reported to be upregulated to varying degrees in several renal diseases according to the literature; there are also studies exploring the interactive correlation between kidney diseases and cell senescence, leading to progressive deterioration of renal function. , Certain differences in excretions of NAG and β-GAL in various stages of several different diseases, especially renal lesions, were enumerated in many articles as well. ,− Therefore, the simultaneous determination of NAG and β-GAL can be greatly meaningful, which contributes to ascertaining the duration and severity of lesions, discriminating between various kinds of kidney disorders, estimating the clinical outcome, and monitoring responses during the whole process from early detection to longitudinal tracking for later treatment.…”

“…12 Finding correlations between NAG and other biomarkers can help for further differentiation and follow-up inspection of diseases. 12 Senescence-associated β-GAL has been reported to be upregulated to varying degrees in several renal diseases according to the literature; 13 there are also studies exploring the interactive correlation between kidney diseases and cell senescence, leading to progressive deterioration of renal function. 13,14 Certain differences in excretions of NAG and β-GAL in various stages of several different diseases, especially renal lesions, were enumerated in many articles as well.…”