Renal interstitial fibrosis is a common pathway for the progression of chronic kidney disease (CKD) to end-stage renal disease. Renalase, acting as a signaling molecule, has been reported to have cardiovascular and renal protective effects. However, its role in renal fibrosis remains unknown. In this study, we evaluated the therapeutic efficacy of renalase in rats with complete unilateral ureteral obstruction (UUO) and examined the inhibitory effects of renalase on transforming growth factor-β1 (TGF-β1)-induced epithelial–mesenchymal transition (EMT) in human proximal renal tubular epithelial (HK-2) cells. We found that in the UUO model, the expression of renalase was markedly downregulated and adenoviral-mediated expression of renalase significantly attenuated renal interstitial fibrosis, as evidenced by the maintenance of E-cadherin expression and suppressed expression of α-smooth muscle actin (α-SMA), fibronectin and collagen-I. In vitro, renalase inhibited TGF-β1-mediated upregulation of α-SMA and downregulation of E-cadherin. Increased levels of Phospho-extracellular regulated protein kinases (p-ERK1/2) in TGF-β1-stimulated cells were reversed by renalase cotreatment. When ERK1 was overexpressed, the inhibition of TGF-β1-induced EMT and fibrosis mediated by renalase was attenuated. Our study provides the first evidence that renalase can ameliorate renal interstitial fibrosis by suppression of tubular EMT through inhibition of the ERK pathway. These results suggest that renalase has potential renoprotective effects in renal interstitial fibrosis and may be an effective agent for slowing CKD progression.

We determined the effect of indoxyl sulfate (IS) on Pit-1 expression and the role of Pit-1 in IS-induced osteoblastic differentiation and calcification of vascular smooth muscle cells (VSMCs). To assess osteoblastic differentiation and Pit-1 expression, VSMCs were incubated with various concentrations of IS for different durations. Phosphonoformic acid (PFA), a competitive inhibitor of Pit-1, was used to verify the role of Pit-1. Western blot analysis and quantitative real-time polymerase chain reaction (PCR) were performed to assess Pit-1 protein and mRNA levels, respectively. To evaluate calcification, calcium content was measured. After IS treatment, we observed osteoblastic differentiation and calcification of VSMCs and up-regulation of Pit-1 expression. Moreover, the effect of IS on osteoblastic differentiation and Pit-1 expression was partly dose- and time-dependent. PFA abrogated the IS-induced osteoblastic differentiation and calcification of VSMCs to a certain extent. The c-Jun N-terminal kinase (JNK) pathway was activated after treatment with IS, whereas inhibition of the JNK pathway partially attenuated the effect of IS on both the stimulation of Pit-1 expression and calcium deposition. Our study is the first to demonstrate that IS promotes Pit-1 expression in part by activation of the JNK pathway that is involved in the mechanism of IS-induced osteoblastic differentiation and matrix mineralization.

Significance Statement: Patients with end stage CKD often develop cognitive decline, but whether this is related to the underlying disease or to hemodialysis remains unclear. We performed three-dimensional pseudocontinuous arterial spin labeling and quantitative susceptibility mapping prospectively in 40 patients with stage 1–4 CKD, 47 nondialysis patients with stage 5 CKD, and 44 healthy controls. Our magnetic resonance imaging data demonstrate that changes in cerebral blood flow–susceptibility coupling might underlie this cognitive decline, perhaps in the hippocampus and thalamus. These results suggest that magnetic resonance imaging parameters are potential biomarkers of cognitive decline in patients with CKD. Moreover, our findings may lead to discovery of novel therapeutic targets to prevent cognitive decline in patients with CKD. Background: Cerebral blood flow (CBF) and susceptibility values reflect vascular and iron metabolism, providing mechanistic insights into conditions of health and disease. Nondialysis patients with CKD show a cognitive decline, but the pathophysiological mechanisms underlying this remain unclear. Methods: Three-dimensional pseudocontinuous arterial spin labeling and quantitative susceptibility mapping were prospectively performed in 40 patients with stage 1–4 CKD (CKD 1–4), 47 nondialysis patients with stage 5 CKD (CKD 5ND), and 44 healthy controls (HCs). Voxel-based global and regional analyses of CBF, susceptibility values, and vascular-susceptibility coupling were performed. Furthermore, the association between clinical performance and cerebral perfusion and iron deposition was analyzed. Results: For CBF, patients with CKD 5ND had higher normalized CBF in the hippocampus and thalamus than HCs. Patients with CKD 5ND had higher normalized CBF in the hippocampus and thalamus than those with CKD 1–4. The susceptibility values in the hippocampus and thalamus were lower in patients with CKD 5ND than in HCs. Patients with CKD 5ND had higher susceptibility value in the caudate nucleus than those with CKD 1–4. More importantly, patients with CKD 5ND had lower CBF-susceptibility coupling than HCs. In addition, CBF and susceptibility values were significantly associated with clinical performance. Conclusions: Our findings demonstrate a new neuropathological mechanism in patients with CKD, which leads to regional changes in CBF-susceptibility coupling. These changes are related to cognitive decline, providing potential imaging markers for assessing clinical disability and cognitive decline in these patients.

Background/Aims: Serum soluble Klotho (sKlotho) plays a role in cardiovascular disease in some populations. However, information regarding the effect of serum sKlotho on atherosclerosis in patients on maintenance hemodialysis (MHD) is limited. Therefore, we tested the level of serum sKlotho in MHD patients to investigate atherosclerosis disease and determine the relationship between sKlotho and atherosclerosis. Methods: Using cross-sectional research, anthropometric and laboratory data were collected for 330 MHD patients. The levels of serum sKlotho before dialysis were tested by enzyme-linked immunosorbent assay. Carotid intima-middle thickness (cIMT) and the number of carotid artery atherosclerotic plaques were measured by color Doppler ultrasonography. The risk factors of atherosclerosis were explored by multivariate logistic regression analysis. Results: Among 330 MHD patients, the average serum sKlotho was (379.93±143.66) pg/ml. The level of serum sKlotho was positively related to hemoglobin (P< 0.05). It was negatively correlated with systolic pressure, pulse pressure, ultrafiltration volume, serum phosphorus, corrected serum calcium×phosphorus, high-sensitivity C-reactive protein (Hs-CRP), cIMT and carotid atherosclerotic plaque quantity and atherosclerosis (P< 0.05). Multivariate logistic regression analysis showed that age (OR = 1.108, 95% CI = 1.067 ∼ 1.151, P = 0.000), dry weight (OR = 1.050, 95% CI = 1.014 ∼ 1.088, P = 0.007), Hs-CRP (OR = 1.126, 95% CI = 1.005 ∼ 1.261, P = 0.041), and serum sKlotho (OR = 0.997, 95% CI = 0.995 ∼ 1.000, P = 0.032) were risk factors for atherosclerosis in MHD patients. Conclusion: Serum sKlotho was related to systolic pressure, pulse pressure, ultrafiltration volume, hemoglobin, serum phosphorus, corrected serum calcium×phosphorus, Hs-CRP, increased cIMT, carotid atherosclerotic plaque quantity and atherosclerosis. Age, dry weight, Hs-CRP, and serum sKlotho were risk factors for atherosclerosis in MHD patients. Serum sKlotho may be a novel risk factor for atherosclerosis in MHD patients.