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Objective·To investigate the effect of icariin on the transition from acute kidney disease (AKI) to chronic kidney disease (CKD) in mice and the possible mechanism.Methods·C57BL/6 mice were intraperitoneally injected with aristolochic acid for 2 weeks to mimic AKI to CKD transition. Icariin was intragastrically administered for 2 or 5 weeks at the end of 2 weeks of aristolochic acid injection or 1 week before modeling. The renal function and pathological injury of the mice were monitored. The mitochondrial structure of renal tubular epithelial cells was observed by transmission electron microscopy. The indexes related to fatty acid oxidative metabolic pathway, fibrosis, and inflammation were detected by quantitative PCR (qPCR) and immunohistochemical staining. The rat renal fibroblast cell line and the rat renal tubular epithelial cell lines were co-cultured in Transwell cell chambers to simulate the interaction between the two types of cells. The renal tubular epithelial cells were pretreated with icariin for 1 h, and then treated with aristolochic acid for 24 h. After removing the two drugs, the renal tubular epithelial cells and the fibroblasts were co-cultured for 24 h. The mRNA or protein expression levels of peroxisome proliferator-activated receptor α (Ppara), pro-fibrotic factors, inflammatory factors, activated caspase-3 (cleaved caspase-3), and extracellular matrix-associated genes in renal fibroblasts were detected by qPCR or Western blotting. The renal tubular epithelial cells were transfected with Ppara-siRNA to observe the expression changes of cleaved caspase-3 and the related indicators of mitochondrial fatty acid oxidative metabolism in the downstream of PPARα after icariin intervention prior to aristolochic acid.Results·Compared with the control group, the serum creatinine and urea nitrogen levels of the mice injected with aristolochic acid only were significantly higher, with a large number of inflammatory cells infiltrating into the kidney and serious renal tubular injury at the end of 2 weeks of aristolochic acid injection and 2 weeks after the last injection (4 weeks). The renal function was significantly improved, and the pathological damage was attenuated in the mice pretreated with icariin. After 4 weeks of modeling, the mitochondrial structure of renal tubular epithelial cells was seriously damaged in the aristolochic acid group, and the mRNA levels of fatty acid oxidative metabolic pathway-related genes were significantly downregulated, compared to the control group, accompanied by macrophage infiltration and renal fibrosis. Icariin pretreatment attenuated these damages generated by aristolochic acid. The serum creatinine and urea nitrogen levels, renal pathological injury, and fibrotic markers of the mice treated with icariin at the end of 2 weeks of aristolochic acid injection showed no difference from the aristolochic acid group. In the in vitro experiments, aristolochic acid treatment suppressed Ppara mRNA expression and elevated cleaved caspase-3, inflammatory factors, and pro-fibrotic factors in renal tubular epithelial cells. It also upregulated the expression of extracellular matrix-related genes in co-cultured renal fibroblasts. In contrast, icariin pretreatment abrogated the changes caused by aristolochic acid. The knockdown of Ppara by siRNA in renal tubular epithelial cells removed the preventive effects of icariin on aristolochic acid inhibiting fatty acid oxidative metabolism and promoting cell apoptosis.Conclusion·Icariin prevents AKI to CKD transition induced by aristolochic acid in mice. It may play its protective role by improving the mitochondrial fatty acid oxidative metabolic pathway, especially through PPARα, in renal tubular epithelial cells.

Objective To analyze the epidemiological characteristics of high-risk populations for chronic kidney diseases (CKD) based on the screening data of community health centers in Jing'an and Minhang Districts of Shanghai from 2016 to 2018. Methods The screening data of high-risk CKD population in community health service centers in Jing'an and Minhang Districts of Shanghai were collected. The differences in the detection rate of CKD among high-risk population with different gender, age and disease history were compared and the influencing factors were analyzed. Results The detection rate of CKD in high-risk population in community was 14.71%, and those with early CKD (stage 1 and 2) accounted for the majority (84.57%). The detection rate of CKD was higher in the female high-risk group than the male group (Chi-square=202.158, P < 0.01), and in the elderly group than the non-elderly group (Chi-square=16.294, P < 0.01). The subjected high-risk individuals had complicated medical history, and those (61.77%) having a history of hypertension ranked first in number. The detection rate of CKD was higher in the patients with hypertension than those without (Chi-square=67.837, P < 0.01), and in those without diabetes than those with (Chi-square=13.978, P < 0.01). Based on the 6 risk factors (gender, age 65 and above, hypertension, diabetes, hyperuricemia and family history of kidney disease), the highest detection rate was found among the 392 patients with 4 risk factors, with 84 patients (21.43%) having CKD. Conclusion Gender, age, hypertension and diabetes mellitus are the risk factors of CKD, the detection rate of CKD is higher in female population and older people with hypertension but not diabetes.

Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse renal hypertrophy, tubular damage, inflammation, fibrosis, and albuminuria in diabetic mice, indicating a protective role of autophagy in DKD. Autophagy impairment in DKD was associated with the downregulation of unc-51-like autophagy-activating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression and autophagy impairment in diabetic kidneys, resulting in less renal hypertrophy and albuminuria. Furthermore, blockade of p53 attenuated miR-214 induction in DKD, leading to higher levels of ULK1 and autophagy, accompanied by an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/ miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD., Introduction Diabetic kidney disease (DKD), a major complication of diabetes mellitus, is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Approximately 30%-40% of patients with [...]

The pathogenesis of ischemic diseases remains unclear. Here we demonstrate the induction of microRNA-668 (miR-668) in ischemic acute kidney injury (AKI) in human patients, mice, and renal tubular cells. The induction was HIF-1 dependent, as HIF-1 deficiency in cells and kidney proximal tubules attenuated miR-668 expression. We further identified a functional HIF-1 binding site in the miR-668 gene promoter. Anti-miR-668 increased apoptosis in renal tubular cells and enhanced ischemic AKI in mice, whereas miR-668 mimic was protective. Mechanistically, anti-miR-668 induced mitochondrial fragmentation, whereas miR-668 blocked mitochondrial fragmentation during hypoxia. We analyzed miR-668 target genes through immunoprecipitation of microRNA-induced silencing complexes followed by RNA deep sequencing and identified 124 protein-coding genes as likely targets of miR-668. Among these genes, only mitochondrial protein 18 kDa (MTP18) has been implicated in mitochondrial dynamics. In renal cells and mouse kidneys, miR-668 mimic suppressed MTP18, whereas antimiR-668 increased MTP18 expression. Luciferase microRNA target reporter assay further verified MTP18 as a direct target of miR-668. In renal tubular cells, knockdown of MTP18 suppressed mitochondrial fragmentation and apoptosis. Together, the results suggest that miR-668 is induced via HIF-1 in ischemic AKI and that, upon induction, miR-668 represses MTP18 to preserve mitochondrial dynamics for renal tubular cell survival and kidney protection., IntroductionTissue damage by ischemia/reperfusion leads to the development of a major class of disease, called ischemic disease, including myocardial infarction, stroke, shock liver, and acute kidney injury (AKI). Despite decades [...]

Adult autosomal dominant polycystic kidney disease (ADPKD) has been shown to be related as a "third hit" to the occurrence of acute or chronic kidney injury. Here, we examined whether dehydration, as a common kidney risk factor, could cause cystogenesis in chronic-onset Pkd1−/− mice by regulating macrophage activation. First, we confirmed that dehydration accelerated cytogenesis in Pkd1−/− mice and that macrophages infiltrated the kidney tissues even earlier than macroscopic cyst formation. Then, microarray analysis suggested that glycolysis pathway may be involved in macrophage activation in Pkd1−/− kidneys under conditions of dehydration. Further, we confirmed glycolysis pathway was activated and lactic acid (L-LA) was overproduced in the Pkd1−/− kidney under conditions of dehydration. We have already proved that L-LA strongly stimulated M2 macrophage polarization and overproduction of polyamine in macrophage in vitro, and in the present study, we further discovered that M2 polarization-induced polyamine production shortened the primary cilia length by disrupting the PC1/PC2 complex. Finally, the activation of L-LA–arginase 1–polyamine pathway contributed to cystogenesis and progressive cyst growth in Pkd1−/− mice recurrently exposed to dehydration. [ABSTRACT FROM AUTHOR]