Cellular Senescence Is Associated with Faster Progression of Focal Segmental Glomerulosclerosis.

BACKGROUND: 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. METHODS: 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. RESULTS: Cell senescence (p16INK4A, SA-ß-galactosidase [SA-ß-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 (p < 0.05-0.01). Tubular SA-ß-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16INK4A was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-ß-Gal and p16INK4A were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16INK4A and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16INK4A, but not SA-ß-Gal, contributed significantly to the prediction of eGFR loss. CONCLUSIONS: The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16INK4A in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS.

Regression of asymptomatic cardiomyopathy and clinical outcome of renal transplant recipients: a long-term prospective cohort study.

BACKGROUND: Asymptomatic left ventricular hypertrophy (LVH) is highly prevalent and associated with an adverse outcome in renal transplant recipients (RTRs). Nonetheless, there are currently no available studies analyzing the effect of LVH regression on solid clinical endpoints in these patients. METHODS: This study is the prospective observational extension of two randomized controlled trials aimed at assessing the effect of active intervention on post-transplant LVH in RTRs. We evaluated the incidence of a composite of death and any cardiovascular (CV) or renal event in 60 RTRs in whom LVH regression was observed and in 40 whose LVH remained unchanged or worsened. RESULTS: During an 8.4 ± 3.5-year follow-up, 8 deaths, 18 CV events and 6 renal events occurred in the entire cohort. Multivariable analysis showed that age [hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.03-1.12 each 1 year, P = 0.002] and LVH regression (HR 0.42, 95% CI 0.22-0.87, P = 0.019) were significant predictors of the composite endpoint. Kaplan-Meier estimates showed better survival rates in patients in whom actual LVH regression was achieved (P < 0.001, log-rank test). Age (HR 1.09, 95% CI 1.03-1.15 each 1 year, P = 0.004), better graft function (HR 0.95, 95% CI 0.91-0.99 each 1 mL/min/1.73 m(2) increase in estimated glomerular filtration rate, P = 0.03) and LVH regression (HR 0.41, 95% CI 0.22-0.79, P = 0.01) were significant predictors of the CV endpoint. Patients with a left ventricular mass index decrease also showed better cardiac event-free survival (P = 0.0022, log-rank test). CONCLUSIONS: This is the first study to demonstrate that LVH regression, regardless of the therapeutic strategy adopted to achieve it, portends better long-term clinical outcome in RTRs.

Enhanced myostatin expression and signalling promote tubulointerstitial inflammation in diabetic nephropathy.

Myostatin (MSTN), a family member of the transforming growth factor (TGF)-ß super family, has been detected in the tubuli of pig kidney, but its role in the human kidney is not known. In this study we observed upregulation of MSTN mRNA (~8 to 10-fold increase) both in the glomeruli and tubulointerstitium in diabetic nephropathy (DN). In DN, immunoreactive MSTN was mainly localized in the tubuli and interstitium (∼4-8 fold increase), where it colocalized in CD45+ cells. MSTN was also upregulated in the glomeruli and the arterial vessels. Tubulointerstitial MSTN expression was directly related to interstitial fibrosis (r = 0.54, p < 0.01). In HK-2 tubular epithelial cells, both high (30 mmol) glucose and glycated albumin upregulated MSTN mRNA and its protein (p < 0.05-0.01). MSTN-treated HK-2 cells underwent decreased proliferation, together with NF-kB activation and CCL-2 and SMAD 2,3 overexpression. In addition, MSTN induced intracellular ROS release and upregulated NADPH oxidase, effects which were mediated by ERK activation. In conclusion, our data show that MSTN is expressed in the human kidney and overexpressed in DN, mainly in the tubulointerstitial compartment. Our results also show that MSTN is a strong inducer of proximal tubule activation and suggest that MSTN overexpression contributes to kidney interstitial fibrosis in DN.

Toll-like receptor-4 signaling mediates inflammation and tissue injury in diabetic nephropathy.

Toll-like receptors (TLRs) are a class of receptors of the innate immune system which detect pathogen-associated and danger-associated molecular patterns in order to initiate an inflammatory response. TLR2 and TLR4 downward signaling causes the production of proinflammatory cytokines that can induce insulin resistance and cardiovascular damage in obesity and type 2 diabetes mellitus. In diabetic nephropathy, TLR4, nucleotide-binding oligomerization domain-containing protein 2 (NOD2), and NLRP3 inflammasome are involved in the production and persistence of inflammation. The activation of TLRs stimulates the expression of several inflammatory cytokines and chemokines such as CCL2 and tumor necrosis factor (TNF)-α, which are associated with the progression of diabetic nephropathy. Different inflammatory mechanisms seem to take place in the early and late stages of diabetic kidney disease, with activation of the innate immunity response and enhanced chemiotactic effects in native kidney cells at an early stage, followed by tubulointerstitial monocyte infiltration at a more advanced disease state. Overall, available data indicate that the upregulated TLR4 response in the kidney translates the metabolic alterations of diabetes into kidney damage.