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Background: For IgA nephropathy (IgAN), tubular atrophy/interstitial fibrosis is the most important prognostic pathological indicator in the mesangial and endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and presence of crescents (MEST-C) score. The identification of non-invasive biomarkers for tubular atrophy/interstitial fibrosis would aid clinical monitoring of IgAN progression and improve patient prognosis., Methods: The study included 188 patients with primary IgAN in separate confirmation and validation cohorts. The associations of miR-92a-3p, miR-425-5p, and miR-185-5p with renal histopathological lesions and prognosis were explored using Spearman correlation analysis and Kaplan-Meier survival curves. Bioinformatics analysis and dual luciferase experiments were used to identify hub genes for miR-185-5p. The fibrotic phenotypes of tubular epithelial cells were evaluated in vivo and in HK-2 cells., Results: miRNA sequencing and cohort validation revealed that the expression levels of miR-92a-3p, miR-425-5p, and miR-185-5p in urine were significantly increased among patients with IgAN; these levels could predict the extent of tubular atrophy/interstitial fibrosis in such patients. The combination of the three biomarkers resulted in an area under the receiver operating characteristic curve of 0.742. The renal prognosis was significantly worse in the miR-185-5p high expression group than in the low expression group (P=0.003). Renal tissue in situ hybridization, bioinformatics analysis, and dual luciferase experiments confirmed that miR-185-5p affects prognosis in patients with IgAN mainly by influencing expression of the target gene tight junction protein 1 (TJP1) in renal tubular epithelial cells. In vitro experiment revealed that an miR-185-5p mimic could reduce TJP1 expression in HK-2 cells, while increasing the levels of α-smooth muscle actin, fibronectin, collagen I, and collagen III; these changes promoted the transformation of renal tubular epithelial cells to a fibrotic phenotype. An miR-185-5p inhibitor can reverse the fibrotic phenotype in renal tubular epithelial cells. In a unilateral ureteral obstruction model, the inhibition of miR-185-5p expression alleviated tubular atrophy/interstitial fibrosis., Conclusion: Urinary miR-185-5p, a non-invasive biomarker of tubular atrophy/interstitial fibrosis in IgAN, may promote the transformation of renal tubular epithelial cells to a fibrotic phenotype via TJP1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Duan, Bu, Liang, Chen, Zhang, Zhang, Li, Chen and Cai.)

Acute kidney injury (AKI) is a clinically common kidney disease. Age is an important factor that contributes to the susceptibility to AKI. Mesenchymal stem cells (MSCs) are a promising therapy for AKI, and miRNAs in exosomes (Exos) derived from MSCs are an important aspect of MSC treatment. However, the therapeutic effect of miRNA from MSC-derived Exos on AKI and the related mechanism have not been fully clarified. Whether there is a relationship between the mechanisms of senescence for AKI susceptibility and the therapeutic effect of MSCs has not been studied. We compared the degree of cisplatin-induced AKI injury in young and elderly mice and investigated changes in the expression of p53 and markers of DNA damage and apoptosis, which are important in both senescence and AKI. Ageing mice exhibited increased expression of p53 and pro-apoptosis markers. Upregulation of the senescence-associated DNA damage/p53 pathway may be an important susceptibility factor for cisplatin-induced AKI. Treatment with MSCs can reduce the degree of DNA damage and suppress p53 expression and apoptosis. Upon screening for differentially expressed miRNAs, let-7b-5p levels were found to be lower in aged mice than in young mice, and MSC treatment increased let-7b-5p levels. The presence of let-7b-5p in MSC-derived Exos alleviates tubular epithelial cell apoptosis by inhibiting p53, which reduces DNA damage and apoptosis pathway activity. Let-7b-5p downregulation may lead to increased renal AKI susceptibility, thus indicating that this miRNA is a potential driver of the MSC treatment response in AKI., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The most prevalent primary glomerulonephritis and leading cause of end-stage renal disease worldwide is IgA nephropathy (IgAN). More and more studies are describing urinary microRNA (miRNA) as a non-invasive marker for a variety of renal diseases. We screened candidate miRNAs based on data from three published IgAN urinary sediment miRNAs chips. In separate confirmation and validation cohorts, we included 174 IgAN patients, 100 patients with other nephropathies as disease controls (DC), and 97 normal controls (NC) for quantitative real-time PCR. A total of three candidate miRNAs, miR-16-5p, Let-7g-5p, miR-15a-5p were obtained. In both the confirmation and validation cohorts, these miRNAs levels were considerably higher in the IgAN than in NC, with miR-16-5p significantly higher than in DC. The area under the ROC curve for urinary miR-16-5p levels was 0.73. Correlation analysis suggested that miR-16-5p was positively correlated with endocapillary hypercellularity (r = 0.164 p = 0.031). When miR-16-5p was combined with eGFR, proteinuria and C4, the AUC value for predicting endocapillary hypercellularity was 0.726. By following the renal function of patients with IgAN, the levels of miR-16-5p were noticeably higher in the IgAN progressors than in the non- progressors (p = 0.036). Urinary sediment miR-16-5p can be used as noninvasive biomarkers for the assessment of endocapillary hypercellularity and diagnosis of IgA nephropathy. Furthermore, urinary miR-16-5p may be predictors of renal progression., (© 2023. The Author(s).)

Acute kidney injury (AKI) is a disease that seriously endangers human health. At present, AKI lacks effective treatment methods, so it is particularly important to find effective treatment measures and targets. Bioinformatics analysis has become an important method to identify significant processes of disease occurrence and development. In this study, we analyzed the public expression profile with bioinformatics analysis to identify differentially expressed genes (DEGs) in two types of common AKI models (ischemia-reperfusion injury and cisplatin). DEGs were predicted in four commonly used microRNA databases, and it was found that miR-466 and miR-709 may play important roles in AKI. Then, we found key nodes through protein-protein interaction (PPI) network analysis and subnetwork analysis. Finally, by detecting the expression levels in the renal tissues of the two established AKI models, we found that Myc, Mcm5, E2f1, Oip5, Mdm2, E2f8, miR-466, and miR-709 may be important genes and miRNAs in the process of AKI damage repair. The findings of our study reveal some candidate genes, miRNAs, and pathways potentially involved in the molecular mechanisms of AKI. These data improve the current understanding of AKI and provide new insight for AKI research and treatment., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2021 Si-Yang Wang et al.)

Stem cell therapy has been applied in many fields. Basic and clinical studies on stem cell therapy for acute kidney injury (AKI) have been conducted. Stem cells have been found to exert renal protection through a variety of mechanisms, such as regulating the immune system and secreting growth factors, cytokines, and extracellular vesicles (EVs). Among them, EVs are considered to be important mediators for stem cell protection because they contain various biological components, including microRNAs (miRNAs). miRNAs are a class of small RNAs that function in posttranscriptional gene regulation. A number of studies have confirmed that miRNAs in stem cell-derived EVs can protect from AKI. miRNAs can enter the injured renal tissue through EVs released from stem cells, thereby exerting anti-inflammatory, anti-apoptotic, anti-fibrotic, and pro-angiogenesis effects on AKI. However, the stem cell sources and AKI models used in these studies have differed. This article will summarize the miRNAs that play a role in kidney protection in stem cell EVs and clarifies the treatment characteristics and mechanisms of different miRNAs. This may provide a reference for clinical practice for acute and chronic kidney diseases.

Recent studies have indicated that urinary sediment miRNAs not only are able to serve as non-invasive diagnostic biomarkers for IgA nephropathy (IgAN) but may also be closely related to several clinical and pathological indicators. However, the lack of a suitable internal reference miRNA has hampered research into urinary sediment miRNAs. To date, U6 has been used as a reference gene in urinary sediment miRNA studies mostly based on the results from studies using tissue samples and cell lines. In a total of 330 IgAN patients, 164 disease control patients and 130 normal control patients, there was no significant difference in U6 levels. We also compared the U6 levels in different types of primary glomerular disease groups (IgA nephropathy, membranous nephropathy, minimal change nephrosis and focal segmental glomerular sclerosis). The results confirmed that there was no significant difference in the expression of U6 in different primary glomerular disease groups. Moreover, treatment had no significant effect on the expression levels of U6 in IgA nephropathy. Therefore, U6 is an excellent housekeeping gene for urinary sediment miRNA studies of IgA nephropathy.

Long non-coding RNA HOTAIR was regarded as an oncogene in multiple cancers. Previous studies have shown that HOTAIR is involved in the proliferation and tumorigenesis of renal carcinoma cells, while microRNA (miR)-217 functions as a tumor suppressor in renal cell carcinoma (Rcc). However, the underlying molecular mechanism of HOTAIR in Rcc, especially in association with miR-217, has not been studied. In this study, we first demonstrated that HOTAIR expression was upregulated, which was correlated with tumor progression, and miR-217 downregulated in Rcc tissues and cells. Importantly, HOTAIR expression was negatively correlated with miR-217 expression in Rcc tissues. Gain- and loss-of-function of HOTAIR revealed that HOTAIR functioned as a ceRNA for miR-217 to facilitate HIF-1α expression and then upregulated AXL level promoting Rcc proliferation, migration, and EMT process, and inhibiting apoptosis. Furthermore, HOTAIR knockdown suppressed tumor growth and reduced the expression of proliferation antigen ki-67, HIF-1α, and AXL, but upregulated the expression of miR-217 in vivo. Finally, with AXL inhibitor BGB324, we confirmed that HOTAIR promoted Rcc activity through AXL signaling both in vitro and in vivo. In conclusion, these results suggest that HOTAIR promotes Rcc tumorigenesis via miR-217/HIF-1α/AXL signaling, which may provide a new target for the diagnosis and therapy of Rcc disease.

Background: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. The clinical spectrum of IgAN varies from minor urinary abnormalities to rapidly progressive renal failure. Evaluation of the disease by repeated renal biopsy is not practical due to its invasive procedure. Urinary sediment miRNAs promise to serve as non-invasive biomarkers to assess kidney injury of IgAN., Methods: Fifty two biopsy-proven IgAN patients and twenty five healthy controls were enrolled in the study. Urinary sediment miRNAs were extracted. Expressions of miR-34a, miR-205, miR-21, miR-146a and miR-155 were quantified by real-time quantitative polymerase chain reaction (RT-QPCR). The receiver operating characteristic (ROC) curve was used to investigate the value of the miRNAs for predicting diagnosis of IgAN and evaluating histopathological injury. The patients were treated according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and followed up. The roles of miRNAs in reflecting therapeutic efficacy and disease progression were analyzed., Results: 1. The IgAN group had significantly lower urinary miR-34a, miR-205, and miR-155, but higher miR-21 levels than controls. The ROC revealed that urinary miR-34a ≤ 0.047, miR-205 ≤ 0.209, miR-21 ≥ 0.461 and miR-155 ≤ 0.002 could distinguish patients with IgAN from healthy ones. In addition, miR-205 ≤ 0.125 and miR-21 ≥ 0.891 can distinguish IgAN patients with severe tubular atrophy/interstitial fibrosis from those with mild tubular atrophy/interstitial fibrosis. 2. After a mean 15.19 months follow-up, the reduction of proteinuria (g/24 h/year) was positively correlated with baseline urinary miR-21 and inversely correlated with miR-205. The levels of baseline eGFR and miR-205 in the complete remission group were significantly higher than non-complete remission group (p < 0.001; p = 0.018), while proteinuria, miR-21 and miR-146a were lower than non-complete remission group (p = 0.002; p = 0.021; p = 0.009). But multivariate analysis revealed that only baseline eGFR correlated with the remission of IgAN (p = 0.001, OR = 1.042)., Conclusions: The levels of some urinary sediment miRNAs, especially baseline miR-21 and miR-205, may be used as potential prognostic markers for evaluating the tubulointerstitial damage of IgAN. Furthermore, baseline levels of urinary miRNAs may be predictors of therapeutic efficacy and disease progression.

Hematuria is one of the basic clinical manifestations of IgA nephropathy (IgAN). Isolated microscopic hematuria or microscopic hematuria combined with proteinuria is risk factor for the long-term prognosis of IgAN. Current evidence of the consequences of glomerular hematuria rests on insights from basic research on the molecular mechanisms of hemoglobin and related reactive oxygen species-induced tubular injury as well as on the clinical evidence of macroscopic hematuria-associated acute kidney injury (AKI) in IgAN. These researches may simply elucidate some effects of macroscopic hematuria but not microscopic hematuria. Recent studies conducted on blood and urinary erythrocytes have made progress. Researches have revealed that mature erythrocytes contain abundant, long, non-coding RNA, miRNA (microRNA) and Y RNA. Among the top 50 expressions of erythrocyte-derived miRNAs, 33 (66%) of them may be the potential urinary biomarkers of IgAN. Moreover, when urinary erythrocytes are compressed while exiting out of an impaired nephron, erythrocyte-derived vesicles (including microvesicles and apoptotic vesicles) may increase. Animal models for hematuria and human biopsy tissues confirm renal parenchymal cells could phagocytose red blood cells and erythrocyte-derived vesicles. These vesicles, which contain miRNAs, may alter the transcriptome of recipient cells and impact the occurrence and development of IgAN., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

The miRNAs in urinary sediment are easy to obtain, which provides a new approach to searching for non-invasive biomarkers of IgA nephropathy (IgAN). Compared with normal controls (n = 3), 214 different miRNAs in the urinary sediment of IgAN (n = 9) were found by miRNA chip assay. By quantitative PCR analysis, miR-25-3p, miR-144-3p and miR-486-5p were confirmed to be significantly higher in IgAN (n = 93) than in the normal group (n = 82) or disease control (n = 40). These three miRNAs had good specificity and sensitivity for the diagnosis of IgAN by receiver operating characteristic curve analysis, in which the AUC value of miR-486-5p was the largest at 0.935. Urinary sediment miR-25-3p, miR-144-3p and miR-486-5p were demonstrated to be mainly derived from urinary erythrocytes, which were separated by CD235a magnetic beads. The increased expression of urinary erythrocyte miRNAs in IgAN patients was not associated with those in the blood erythrocytes. In addition, urinary supernatant microvesicles of miR-144-3p and miR-486-5p in the IgAN group were also significantly increased. This study showed that the miR-25-3p, miR-144-3p and miR-486-5p in urinary sediment were mainly derived from urinary erythrocytes, which could be non-invasive candidate biomarkers for IgA nephropathy.