The cell cycle inhibitor p16(INK4A) (also known as cyclin-dependent kinase inhibitor 2A) is expressed in vivo in many tissues with age. The exposure of certain chronic stresses can trigger p16(INK4A) expression and a senescence-like phenotype. We studied whether p16(INK4A) expression is induced in glomerular disease (GD). We performed p16(INK4A) immunostaining on 35 biopsies with GD, 12 tubulointerstitial nephritis (TIN), and 19 normal live donor kidneys at transplantation. Based on values for 42 normal kidneys, we calculated expected nuclear p16(INK4A) expression for age and compared the observed values in diseased kidneys to those expected for age. In GD, p16(INK4A) expression was strikingly increased in glomerular and interstitial cell nuclei compared to normals and TIN, and could not be attributed to age (P<0.05). By multivariate analyses, GD was independently associated with increased nuclear p16(INK4a) expression in glomeruli (P<0.001) and interstitium (P=0.01). The p16(INK4A) expression in glomerular and interstitial cell nuclei, and tubular cytoplasm was higher in kidneys with proteinuria and with atrophy/fibrosis (P<0.05). Older age was associated with increased nuclear p16(INK4a) expression in tubules (P=0.01), and interstitial inflammation was associated with increased nuclear p16(INK4a) expression in interstitial cells (P=0.001). The p16(INK4a) staining in tubular cytoplasm was increased in both GD and TIN compared to normals (P<0.001), and was not related to age (P>0.05). Thus, kidneys with GD display increased expression of senescence marker p16(INK4A) in glomerular and interstitial cell nuclei compared to kidneys with normal aging or TIN. The findings suggest a role for somatic cell senescence mechanisms in progression of GD.
Arteriolar hyaline thickening (AH) is the most characteristic lesion of chronic calcineurin inhibitor nephrotoxicity. This study was performed to compare the inter-observer reproducibility of AH scoring using Banff criteria and a newly proposed criterion. Forty-five nonprotocol post-transplant biopsies from 38 patients immunosuppressed with tacrolimus or cyclosporine A (CsA) were included. The severity of AH was blindly scored by three observers. According to the new criteria, AH is graded based on circular vs. noncircular involvement and the number of arterioles involved. The kappa statistics were used to assess the inter-observer reproducibility. Twenty-seven (60%) biopsies showed AH. The AH grades by both criteria were correlated with serum creatinine at biopsy and inversely correlated with estimated glomerular filtration rate (GFR) (p < 0.05). The recent AH criteria improved the mean pairwise agreement (79.4% vs. 68%) and the overall kappa value (0.67 vs. 0.52) (p = 0.02) compared to Banff criteria. The mean inter-slide variation using Banff and the new criterion were 23% and 27.6%, respectively (p > 0.05). The new AH criterion results in better inter-observer reproducibility, and is clinically validated against serum creatinine and estimated GFR. There is substantial intra-biopsy variation, therefore, evaluation of more than one section is crucial to determine severity of arteriolar damage more accurately.
Introduction: Diabetic nephropathy (DN) is the most common cause of the chronic kidney disease in the world. Oxidative stress on the other hand has a major and well known role in its pathophysiology. Objectives: The aim of the study is to figure out if tempol, a synthetic antioxidant agent, modifies DN and to determine its relevance to changes of serum oxidative biomarkers. Materials and Methods: Twenty-seven male rats were equally divided in to 4 groups (7 rats for each group). Group I (control or C), group II (diabetic or D), groups III (Tempol) which were given tempol (100 mg/kg/day) by gavages for 28 days and group IV (D&T) which includes diabetic rats that also received same dose of tempol. After treatment, blood samples were isolated. Enzymatic scavengers including catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities, lipid peroxidation (LPO), total antioxidant capacity (TAC) and total thiol molecules (TTM) were measured. Blood urea nitrogen (BUN), creatinine (Cr) an albumin/Cr ratio were evaluated as well. Statistical differences were assessed with one-way analysis of variance (ANOVA) by SPSS followed by Tukey t test. Results: Oxidative stress biomarkers modified and Alb/Cr ratio increased in diabetic group (II), however, they were altered to normal in group IV (D&T) compared with diabetic group (D). Conclusion: Tempol can modify oxidative stress biomarkers and presumably nephropathy in diabetic rats.
BackgroundOne of common mechanisms in pathophysiology of chronic kidney diseases is epithelial-mesenchymal transition (EMT). On the other hand oxidative stress has been known to participate in kidney damage of diabetic nephropathy (DN). ObjectivesWe studied if tempol, a well-known antioxidant agent, can ameliorate EMT in DN induced in male rats. Materials and MethodsTwenty-seven male rats were equally divided in to 4 groups. Group I (control or C), group II (diabetic or D), group III (T) rats which was given tempol (100 mg/kg/day) by gavages for 28 days and group IV (D&T) was diabetic rats that also received same dose of tempol. After treatment, their kidneys were studied by immunohistochemicalstaining. ResultsPathological changes in the kidney were detected concurrently with increasing kidney weight and urinary albumin excretion. In addition, EMT indices, i.e. decline of E-cadherin and increase of α SMA staining were significantly emerged in the renal tubular cells of diabetic group and were partially modified in diabetic group which were simultaneously treated by tempol. ConclusionsTempol can modify, but not significantly, EMT induced by DN.
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