Losartan alleviates renal fibrosis by inhibiting the biomechanical stress-induced epithelial-mesenchymal transition of renal epithelial cells.

Angiotensin receptor blockers (ARBs) have been reported to be beneficial of renal fibrosis, but the molecular and cellular mechanisms are still unclear. In this study, we investigated the effectiveness and relevant mechanism of ARBs in alleviating renal fibrosis, especially by focusing on biomechanical stress-induced epithelial to mesenchymal transition (EMT) of renal epithelial cells. Unilateral ureteral obstruction (UUO) renal fibrosis model was established in mice by ligating the left ureter, and then randomly received losartan at a low dose (1 mg/kg) or a regular dose (3 mg/kg) for 2 weeks. Compared to the control, histological analysis showed that losartan treatment at either a low dose or a regular dose effectively attenuated renal fibrosis in the UUO model. To further understand the mechanism, we ex vivo loaded primary human renal epithelial cells to 50 mmHg hydrostatic pressure. Western blot and immunostaining analyses indicated that the loading to 50 mmHg hydrostatic pressure for 24 h significantly upregulated vimentin, ß-catenin and α-SMA, but downregulated E-cadherin in renal epithelial cells, suggesting the EMT. The addition of 10 or 100 nM losartan in medium effectively attenuated the EMT of renal epithelial cells induced by 50 mmHg hydrostatic pressure loading. Our in vivo and ex vivo experimental data suggest that losartan treatment, even at a low dose can effectively alleviate renal fibrosis in mouse UUO model, at least partly by inhibiting the biomechanical stress-induced EMT of renal epithelial cells. A low dose of ARBs may repurpose for renal fibrosis treatment.

The BACE1-Specific DNA Aptamer A1 Rescues Amyloid-ß Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease.

Amyloid-ß (Aß) plaque deposits in the brain are considered to be one of the main pathological markers of Alzheimer's disease (AD). The sequential proteolytic cleavage of amyloid precursor protein (APP) by the aspartyl proteases ß-site APP-cleaving enzyme 1 (BACE1) and γ-secretase produces Aß. Therefore, BACE1 inhibition is a very attractive target for the treatment of AD. Our previous work identified a DNA aptamer named A1 that can bind to BACE1 with high affinity and specificity and exhibits a distinct inhibitory effect on BACE1 activity in an AD cell model. The purpose of this research was to test the effect of aptamer A1 in Tg6799 mice. Four-month-old Tg6799 mice were randomly divided into two groups and treated with aptamer A1 and ineffective aptamer A1scr, respectively, by intracerebroventricular injection. Subsequent behavioral experiments showed that treatment with the aptamer A1 improved the cognitive abilities of the AD mice. Western blot indicated that BACE1 and soluble amyloid precursor protein ß (sAPPß) expression significantly decreased in the A1-treated mice. Moreover, aptamer A1 reduced the content of Aß42 and the number and density of senile plaques in AD mice. Therefore, our results indicate that aptamer A1 is a novel specific and potent BACE1 inhibitor and is a promising potential target for the treatment of AD.

Potential Role of the Resident Mesenchymal Stem-Like Cells in Renal Fibrogenesis after Ureteral Obstruction.

The mechanisms of renal fibrogenesis after ureteral obstruction remain unclear. We tried to primarily expand mesenchymal stem cells from renal tissues and then investigated their role in fibrogenesis after ureteral obstruction. Unilateral ureteral obstruction was induced by ligating the left ureteral duct of adult C57BL/6 mice. We collected the kidneys for experiments at 2, 7, and 14 days after operation. Histological analysis showed obviously fibrotic changes in the left kidney at 7 days and further increased at 14 days after ureteral obstruction. To expand mesenchymal stem cells, we minced the renal tissues into small explants (about 1 mm3) and cultured onto 10 cm dishes. Interestingly, the outgrowth of cells was observed significantly earlier from the explants of the obstructed left kidney than that of the unobstructed right kidney. These expanded cells showed the potency of adipogenic, osteogenic, and chondrogenic differentiations and positively expressed with CD44 and partly expressed with CD90, CD105, and CD106, but negatively expressed with CD34, CD45, and FSP1, suggesting the phenotype of mesenchymal stem-like cells (MSLCs). The mouse fibrosis RT2 profiler PCR array showed that many genes were changed over 2-fold in the MSLCs expanded from both kidneys at 2, 7, and 14 days after operation. Interestingly, profibrotic genes were prevalently enhanced in the left kidney with ureteral obstruction. Histological analysis also showed obviously infiltration of inflammatory cells in the left kidney at 14 days after operation. Our data indicate the potential role of resident MSLCs in renal fibrogenesis after ureteral obstruction, but further experiments are required to understand the relevant mechanisms.

Recovery of renal function in a heart transplantation recipient with over 300 days of iatrogenic anuria: A case report.

RATIONALE: Anuria is a severe symptom indicating severe kidney damage. Patient recovery from prolonged anuria is rarely reported. PATIENT CONCERNS: A 15-year-old boy received gender- and weight-mismatch heart transplantation (HT) due to dilated cardiomyopathy. He developed severe hypotension, and heart failure 24 hours after surgery, which were relieved by preload reduction treatments. Although, routine examinations did not show any abnormalities in renal function before surgery, anuria occurred 4 days after preload reduction treatments (24-hour urine volume was 23 mL). DIAGNOSIS: The patient was diagnosed with acute kidney injury (AKI). INTERVENTIONS: He was admitted to continuous renal replacement therapy (CRRT) or hemodialysis. OUTCOMES: Surprisingly, his urine volume was gradually, and miraculously, restored to more than 1000 mL/24 hours after over 300 days of anuria. Hemodialysis was not needed in the twentieth month after surgery. Moreover, he partially, recovered renal function. LESSONS: This case indicates the likelihood of recovery from long-term anuria.

[Application of the Oxford classification of IgA nephropathy to predict renal outcome].

OBJECTIVE: To validate the value of the Oxford classification of IgA nephropathy in predicting the renal outcome in Chinese population. METHODS: Retrospective study was done in patients with IgA nephropathy. All slides were re-assessed according to the Oxford classification of IgA nephropathy. The primary end point is doubling serum creatinine, or a 50% reduction in estimated glomerular filtration rate (eGFR), or end-stage renal disease. Pathologic predictors for the progression to the end point were determined by univariate and multivariate Cox regression. RESULTS: Totally 533 patients were enrolled in the study. During the follow-up (median: 39 months; range: 12-263 months), 5.07% of the patients reached the end point. While tubular atrophy and interstitial fibrosis and arterial/ arteriolar lesion were associated with the endpoint in univariate analysis, only the T score was predictive of the renal outcome in multivariate Cox regression. Combination of the patho- logic lesions had no impact on renal outcome. CONCLUSION: According to the Oxford classification of IgA nephropathy, the degree of tubulointerstitial fibrosis is the only feature independently predictive of renal outcome.

Gene expression of conditioned locomotion and context-specific locomotor sensitization controlled by morphine-associated environment.

The nucleus accumbens (NAc) is involved in contextual drug associations, which might be particularly important for environmental cue-induced relapse to drug seeking. In the present study, rats were first administered repeated morphine for 5 days (5 mg/kg, i.p.) in a contextually paired and unpaired design. After reexposure to the morphine-associated environment, which induced conditioned locomotor activity in the morphine-paired group, we performed a rat 27k 70-mer oligo array to profile gene expression in the NAc. One hundred fifty-five upregulated and 88 downregulated genes were found in the paired group compared with the unpaired group. Eight gene transcripts were then selected to confirm their alterations by quantitative real-time polymerase chain reaction (qRT-PCR). The identified genes generally play important roles in neuroactive receptor-ligand interactions, synapse plasticity, ion transport, and protein phosphorylation. Furthermore, the expression of the eight selected genes that were identified and confirmed to show significant fold changes in the first microarray experiment were again measured with qRT-PCR after morphine challenge (2 mg/kg, i.p.). As expected, 2 mg/kg morphine-induced context-specific sensitization. Meanwhile, mRNA expression of the selected genes showed marked upregulation in the morphine-paired group compared with the unpaired and acute groups. These results suggest that alterations in the expression of the identified genes in the NAc may contribute to the neuroplasticity underlying contextual cue-induced relapse to drug use.