MicroRNAs Associated with Chronic Kidney Disease in the General Population and High-Risk Subgroups-A Systematic Review.

The potential utility of microRNAs (miRNAs) as diagnostic or prognostic biomarkers, as well as therapeutic targets, for chronic kidney disease (CKD) has been advocated. However, studies evaluating the expression profile of the same miRNA signatures in CKD report contradictory findings. This review aimed to characterize miRNAs associated with CKD and/or measures of kidney function and kidney damage in the general population, and also in high-risk subgroups, including people with hypertension (HTN), diabetes mellitus (DM) and human immunodeficiency virus (HIV) infection. Medline via PubMed, Scopus, Web of Science, and EBSCOhost databases were searched to identify relevant studies published in English or French languages on or before 30 September 2022. A total of 75 studies fulfilled the eligibility criteria: CKD (n = 18), diabetic kidney disease (DKD) (n = 51) and HTN-associated CKD (n = 6), with no study reporting on miRNA profiles in people with HIV-associated nephropathy. In individuals with CKD, miR-126 and miR-223 were consistently downregulated, whilst in DKD, miR-21 and miR-29b were consistently upregulated and miR-30e and let-7a were consistently downregulated in at least three studies. These findings suggest that these miRNAs may be involved in the pathogenesis of CKD and therefore invites further research to explore their clinical utility for CKD prevention and control.

Two novel microRNAs and their association with absolute blood pressure parameters in an urban South African community.

MicroRNAs are important in development of disease, and description of novel microRNAs adds to the pool of microRNAs that can be targeted for diagnostic and therapeutic purposes in disease. Herein, we aimed to describe novel microRNAs in a normotensive and hypertensive African population and relate their expression to blood pressure parameters and hypertension status. Previous work using next-generation sequencing showed differential expression of two novel microRNAs in the blood of normotensives and hypertensives. Herein, we have investigated these novel microRNAs by quantitative reverse transcription polymerase chain reaction in a cohort of 881 participants in this study. The relationship between the novel microRNAs and systolic and diastolic blood pressure as well as mean arterial pressure was also investigated. Age and sex-adjusted Spearman's correlations were used to assess the relationship between microRNAs and cardiovascular risk profile variables whilst multivariable logistic regression models were used to assess the association of microRNAs with screen-detected and known hypertension. The novel microRNAs (miR-novel-chr1_36178 and miR-novel-chr15_18383) were significantly dysregulated by hypertension status. The expression of miR-novel-chr1_36178 differed according to sex, correlated with mean arterial pressure and systolic and diastolic blood pressure at higher levels of expression and was associated with screen-detected hypertension. The association of miR-novel-chr1_36178 expression with mean arterial pressure and systolic and diastolic blood pressure, as well as its dysregulation according to hypertension status suggests its possible utility as a biomarker target for hypertension diagnosis and/or therapeutics. Furthermore, its association with screen detected hypertension and dose-response relationship with blood pressure suggests it may be used to identify and monitor individuals at risk of hypertension.

Investigating the altered expression of miR-486-5p and miR-novel-chr1_40444 in dysglycemia in a South African population.

AIMS: This study aims to investigate miR-486-5p and miR-novel-chr1_40444 expressions in dysglycemic individuals. Validating RNA-sequencing findings in a larger sample via reverse transcription qPCR (RT-qPCR), we aim to address global diagnostic and screening limitations, using an African cohort as an example. MATERIALS AND METHODS: This cross-sectional study involved 1,271 individuals [normoglycemic (n = 974), prediabetic (n = 206), screen-detected type 2 diabetes (n = 91)] from the ongoing Vascular and Metabolic Health (VMH) study in Cape Town, South Africa. Whole blood miRNA expression was assessed using TaqMan-based RT-qPCR, with data normalized to an endogenous control (miR-16-5p). RESULTS: Significant underexpression was observed in prediabetes vs normoglycemia for miR-486-5p (P = 0.038), whilst both miRNAs demonstrated significant upregulation in screen-detected type 2 diabetes vs normoglycemia (miR-486-5p, P = 0.009; miR-novel-chr1_40444, P < 0.001), and screen-detected type 2 diabetes in comparison with prediabetes (miR-486-5p, P < 0.001; miR-novel-chr1_40444, P < 0.001). Multivariable regression analyses revealed pronounced interrelations between miR-novel-chr1_40444 and screen-detected type 2 diabetes in unadjusted and adjusted models (Model 1: P < 0.001, Model 2: P < 0.001, Model 3: P = 0.030). Moreover, receiver operating characteristic (ROC) curves revealed significantly enhanced diagnostic capabilities for screen-detected type 2 diabetes vs either normoglycemia (AUC = 0.971, P < 0.001), non-diabetes (AUC = 0.959, P < 0.001), or prediabetes (AUC = 0.902, P < 0.001) when combining the miRNAs with 2 h postprandial glucose. CONCLUSIONS: This study demonstrated the enhanced power of incorporating miRNAs with traditional markers in distinguishing screen-detected type 2 diabetes, warranting further investigations on their unique role in the development of type 2 diabetes.

Expression of whole blood miR-126-3p, -30a-5p, -1299, -182-5p and -30e-3p in chronic kidney disease in a South African community-based sample.

The burden of chronic kidney disease (CKD) in Africa remains poorly characterized, due partly to the lack of appropriate diagnostic strategies. Although in recent years the diagnostic and prognostic utility of microRNAs (miRNAs) have gained prominence in the context of CKD, its value has not been evaluated in African populations. We investigated the expression of whole blood miRNAs (miR-126-3p, -30a-5p, -1299, -182-5p and -30e-3p) in a total sample of 1449 comprising of 13.3% individuals with CKD (stage 1-5) and 26.4% male participants, as well as the association of these miRNAs with prevalent CKD, in a community-based sample of South African adults. We used Reverse Transcription Quantitative Real-Time PCR (RT-qPCR) to analyze miRNA expression. There was an increased expression in whole blood miR-126-3p, -30a-5p, -1299 and -182-5p in individuals with CKD, compared to those without (all p ≤ 0.036), whereas miR-30e-3p showed no significant difference between the groups (p = 0.482). Only miR-126-3p, -182-5p and -30e-3p were independently associated with increased risk of CKD (all p ≤ 0.022). This study showed for the first time that there is a dysregulation of whole blood miR-126-3p, -30a-5p, -1299 and -182-5p in South Africans of mixed-ancestry with CKD. More research is needed to ascertain their role in CKD risk screening in African populations.

MicroRNAs-1299, -126-3p and -30e-3p as Potential Diagnostic Biomarkers for Prediabetes.

This cross-sectional study investigated the association of miR-1299, -126-3p and -30e-3p with and their diagnostic capability for dysglycaemia in 1273 (men, n = 345) South Africans, aged >20 years. Glycaemic status was assessed by oral glucose tolerance test (OGTT). Whole blood microRNA (miRNA) expressions were assessed using TaqMan-based reverse transcription quantitative-PCR (RT-qPCR). Receiver operating characteristic (ROC) curves assessed the ability of each miRNA to discriminate dysglycaemia, while multivariable logistic regression analyses linked expression with dysglycaemia. In all, 207 (16.2%) and 94 (7.4%) participants had prediabetes and type 2 diabetes mellitus (T2DM), respectively. All three miRNAs were significantly highly expressed in individuals with prediabetes compared to normotolerant patients, p < 0.001. miR-30e-3p and miR-126-3p were also significantly more expressed in T2DM versus normotolerant patients, p < 0.001. In multivariable logistic regressions, the three miRNAs were consistently and continuously associated with prediabetes, while only miR-126-3p was associated with T2DM. The ROC analysis indicated all three miRNAs had a significant overall predictive ability to diagnose prediabetes, diabetes and the combination of both (dysglycaemia), with the area under the receiver operating characteristic curve (AUC) being significantly higher for miR-126-3p in prediabetes. For prediabetes diagnosis, miR-126-3p (AUC = 0.760) outperformed HbA1c (AUC = 0.695), p = 0.042. These results suggest that miR-1299, -126-3p and -30e-3p are associated with prediabetes, and measuring miR-126-3p could potentially contribute to diabetes risk screening strategies.

MicroRNA Profiles in Normotensive and Hypertensive South African Individuals.

Hypertension has a complex pathogenesis and symptoms appear in advanced disease. Dysregulation of gene expression regulatory factors like microRNAs has been reported in disease development. Identifying biomarkers which could help understand the pathogenesis and prognosis of hypertension is essential. The study's objective was to investigate microRNA expression profiles according to participant blood pressure status. Next generation sequencing was used to identify microRNAs in the whole blood of 48 body mass index-, smoking- and age-matched normotensive (n = 12), screen-detected hypertensive (n = 16) and known hypertensive (n = 20) female participants. Quantitative reverse transcription polymerase chain reaction was used to validate the next generation sequencing findings in a larger, independent sample of 84 men and 179 women. Using next generation sequencing, 30 dysregulated microRNAs were identified and miR-1299 and miR-30a-5p were the most significantly differentially expressed. Both microRNAs were upregulated in known hypertensives or screen-detected hypertensives compared to the normotensives. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated possible involvement of platelet activation, calcium signaling and aldosterone synthesis pathways. Further validation of miR-1299 and miR-30a-5p using quantitative reverse transcription polymerase chain reaction confirmed sequencing results while yielding new findings. These findings demonstrate microRNA dysregulation in hypertension and their expression may be related to genes and biological pathways essential for blood pressure homeostasis.

Expression Profiles of Circulating microRNAs in South African Type 2 Diabetic Individuals on Treatment.

Aim: The influence of disease duration and anti-diabetic treatment on epigenetic processes has been described, with limited focus on interactions with microRNAs (miRNAs). miRNAs have been found to play key roles in the regulation of pathways associated with type 2 diabetes mellitus (T2DM), and expression patterns in response to treatment may further promote their use as therapeutic targets in T2DM and its associated complications. We therefore aimed to investigate the expressions of circulating miRNAs (miR-30a-5p, miR-1299, miR-182-5p, miR-30e-3p and miR-126-3p) in newly diagnosed and known diabetics on treatment, in South Africa. Methods: A total of 1254 participants with an average age of 53.8years were included in the study and classified according to glycaemic status (974 normotolerant, 92 screen-detected diabetes and 188 known diabetes). Whole blood levels of miR-30a-5p, miR-1299, miR-182-5p, miR-30e-3p and miR-126-3p were quantitated using RT-qPCR. Expression analysis was performed and compared across groups. Results: All miRNAs were significantly overexpressed in subjects with known diabetes when compared to normotolerant individuals, as well as known diabetics vs. screen-detected (p<0.001). Upon performing regression analysis, of all miRNAs, only miR-182-5p remained associated with the duration of the disease after adjustment for type of treatment (OR: 0.127, CI: 0.018-0.236, p=0.023). Conclusion: Our findings revealed important associations and altered expression patterns of miR-30a-5p, miR-1299, miR-182-5p, miR-30e-3p and miR-126-3p in known diabetics on anti-diabetic treatment compared to newly diagnosed individuals. Additionally, miR-182-5p expression decreased with increasing duration of T2DM. Further studies are, however, recommended to shed light on the involvement of the miRNA in insulin signalling and glucose homeostasis, to endorse its use as a therapeutic target in DM and its associated complications.

Circulating Levels of MicroRNAs Associated With Hypertension: A Cross-Sectional Study in Male and Female South African Participants.

MicroRNAs are non-coding, post-transcriptional regulators of gene expression and their dysregulation has been associated with development of various diseases, including hypertension. Consequently, understanding their role in the pathogenesis and progression of disease is essential. Prior research focusing on microRNAs in disease has provided a basis for understanding disease prognosis and offered possible channels for therapeutic interventions. Herein, we aimed to investigate possible differences in the expression profiles of five microRNAs in the blood of participants grouped on the basis of their hypertension status. This was done to elucidate the possible roles played by these microRNAs in the development of hypertension. Using quantitative reverse transcription polymerase chain reaction, we evaluated the expression levels of miR-126-3p, 30a-5p, 182-5p, 30e-3p, and 1299 in the whole blood of 1456 participants, normotensive (n = 573), screen-detected hypertensive (n = 304) and known hypertensive (n = 579). The expression of miR-126-3p and 182-5p was significantly higher in known hypertensives relative to both screen-detected hypertensives and normotensives, and also in screen-detected hypertensives vs normotensives. A significant association between the expression of miR-126-3p, 182-5p, and 30a-5p and known hypertension was also evident. This study demonstrated dysregulated miR-126-3p, 182-5p, and 30a-5p expression in hypertension, highlighting the possible efficacy of these microRNAs as targets for the diagnosis of hypertension as well as the development of microRNA-based therapies.

Circulating miR-30a-5p and miR-182-5p in Prediabetes and Screen-Detected Diabetes Mellitus.

BACKGROUND: microRNAs (miRNAs) have been touted as potential diagnostic and prognostic biomarkers for various diseases. The aim of the present study was to evaluate the diagnostic value of miR-30a-5p and miR-182-5p for prediabetes and screen-detected type 2 diabetes mellitus (T2DM). METHODS: The study included 1270 participants (207 prediabetes, 94 screen-detected diabetes and 969 normotolerant) from the Vascular and Metabolic Health (VMH) study. Whole blood levels of miR-30a-5p and miR-182-5p were quantitated by RT-qPCR. Multivariable logistic regressions were used to relate miRNAs with prediabetes or T2DM and receiver operating characteristic (ROC) curves were used to evaluate the ability of each miRNA to diagnose these conditions. RESULTS: Both miRNAs were significantly highly expressed in individuals with prediabetes or T2DM (both ≥3.2-fold, and p<0.001). We also observed significant under-expression in T2DM relative to prediabetes for miR-182-5p (0.49-fold, p=0.001). Age, sex and BMI-adjusted partial correlation coefficient analysis revealed a significant correlation between the two miRNAs across glucose tolerance statuses (r≥0.932, p<0.001). In normotolerant individuals, both miRNAs showed a negative correlation with waist circumference and positive correlation with HDL-cholesterol whilst in T2DM they correlated positively with hip circumference, 2-hour insulin, HDL- and LDL-cholesterol. Multivariable logistic regressions revealed both miRNAs to be consistently and continuously associated with prediabetes or T2DM (OR≥1.18, 95% 95% CI: 1.10-1.28, p<0.001), while only miR-182-5p associated with a reduced prevalence of T2DM relative to prediabetes (OR: 0.89, 95% CI: 0.83-0.96, p=0.003). In ROC analyses, miR-182-5p almost outperformed HbA1c in diagnosing prediabetes; area under the curve 0.74 vs 0.69. CONCLUSION: Our findings demonstrate that miR-30a-5p and miR-182-5p are associated with dysglycaemia and could potentially predict prediabetes, particularly miR-182-5p.