Clinical application of microRNAs in glomerular diseases.

RNA interference (RNAi) occurs in all organisms and modulates most, if not all, biological pathways. It is the process by which non-coding RNAs, including microRNAs (miRNAs), regulate gene transcription and post-transcriptional processing of messenger RNA (mRNA). A single miRNA can modulate several genes within a cell, and several miRNAs can regulate expression of the same gene, adding tiers of complexity to the regulation of gene expression.

MicroRNA-23b-3p Deletion Induces an IgA Nephropathy-like Disease Associated with Dysregulated Mucosal IgA Synthesis.

Background: IgA nephropathy (IgAN) is the most common primary GN worldwide. Circulating immune complexes form that are prone to deposition in the mesangium, where they trigger glomerular inflammation. A growing body of evidence suggests that dysregulated expression of microRNAs in IgAN may play a significant role in establishing the disease phenotype.

A Pilot Study to Predict Risk of IgA Nephropathy Progression Based on miR-204 Expression.

Introduction: Immunoglobulin (Ig)A nephropathy (IgAN) is the most frequently diagnosed primary glomerulonephritis worldwide. Despite the common diagnostic feature of mesangial IgA-containing immune complex deposition, the clinical course of the disease is extremely variable, with 30% of patients developing end-stage kidney disease within 20 years of diagnosis. Therefore, identifying which patients are likely to progress is paramount.

Hepatic cysteine sulphinic acid decarboxylase depletion and defective taurine metabolism in a rat partial nephrectomy model of chronic kidney disease.

Background: Taurine depletion occurs in patients with end-stage chronic kidney disease (CKD). In contrast, in the absence of CKD, plasma taurine is reported to increase following dietary L-glutamine supplementation. This study tested the hypothesis that taurine biosynthesis decreases in a rat CKD model, but is rectified by L-glutamine supplementation.

The Non-Coding RNA Landscape in IgA Nephropathy-Where Are We in 2021?

IgA nephropathy (IgAN) is the most commonly diagnosed primary glomerulonephritis worldwide. It is a slow progressing disease with approximately 30% of cases reaching end-stage kidney disease within 20 years of diagnosis. It is currently only diagnosed by an invasive biopsy and treatment options are limited.

Differential expression of microRNA miR-150-5p in IgA nephropathy as a potential mediator and marker of disease progression.

Understanding why certain patients with IgA nephropathy progress to kidney failure while others maintain normal kidney function remains a major unanswered question. To help answer this, we performed miRNome profiling by next generation sequencing of kidney biopsies in order to identify microRNAs specifically associated with the risk of IgA nephropathy progression. Following sequencing and validation in independent cohorts, four microRNAs (-150-5p, -155-5p, -146b-5p, -135a-5p) were found to be differentially expressed in IgA nephropathy progressors compared to non-progressors, and patients with thin membrane nephropathy, lupus nephritis and membranous nephropathy, and correlated with estimated glomerular filtration rate, proteinuria, and the Oxford MEST-C scores (five histological features that are independent predictors of clinical outcome).

Macrophage interactions with collecting duct epithelial cells are capable of driving tubulointerstitial inflammation and fibrosis in immunoglobulin A nephropathy.

Background: Tubulointerstitial fibrosis is a powerful predictor of future progression inimmunoglobulin A (IgA) nephropathy (IgAN). Proximal tubular epithelial cells (PTECs), in concert with infiltrating macrophages, are regarded as the agents provocateurs for driving this fibrotic process. However, evidence is now emerging for a contributory role of the distal nephron.

Vesicles bearing gifts: the functional importance of micro-RNA transfer in extracellular vesicles in chronic kidney disease.

Extracellular vesicles (EVs), including microparticles (MPs) and exosomes (EXOs), are derived from a wide range of mammalian cells including blood platelets, endothelial cells, and kidney cells and can be detected in body fluids including blood and urine. While EVs are well established as diagnostic markers under pathophysiological and stress conditions, there is also mounting evidence of their functional significance as vehicles for communication between cells mediated by the presence of nucleic acids, especially microRNAs (miRs), encapsulated in the EVs. miRs regulate gene expression, are transported both in MPs and EXOs, and exert profound effects in the kidney.

MicroRNAs: a new avenue to understand, investigate and treat immunoglobulin A nephropathy?

IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis worldwide. Up to 30% of cases develop the progressive form of the disease, eventually requiring renal replacement therapy. Diagnosis and risk stratification relies on an invasive kidney biopsy and management options are limited, with recurrence following renal transplantation being common.

β1,4-galactosyltransferase 1 is a novel receptor for IgA in human mesangial cells.

IgA nephropathy is characterized by mesangial deposition of IgA, mesangial cell proliferation, and extracellular matrix production. Mesangial cells bind IgA, but the identity of all potential receptors involved remains incomplete. The transferrin receptor (CD71) acts as a mesangial cell IgA receptor and its expression is upregulated in many forms of glomerulonephritis, including IgA nephropathy.

Sialic acid supplementation ameliorates puromycin aminonucleoside nephrosis in rats.

Defects in sialylation are known to have serious consequences on podocyte function leading to collapse of the glomerular filtration barrier and the development of proteinuria. However, the cellular processes underlying aberrant sialylation in renal disease are inadequately defined. We have shown in cultured human podocytes that puromycin aminonucleoside (PAN) downregulates enzymes involved in sialic acid metabolism and redox homeostasis and these can be rescued by co-treatment with free sialic acid.

The effect of albumin on podocytes: the role of the fatty acid moiety and the potential role of CD36 scavenger receptor.

Evidence is emerging that podocytes are able to endocytose proteins such as albumin using kinetics consistent with a receptor-mediated process. To date the role of the fatty acid moiety on albumin uptake kinetics has not been delineated and the receptor responsible for uptake is yet to be identified. Albumin uptake studies were carried out on cultured human podocytes exposed to FITC-labelled human serum albumin either carrying fatty acids (HSA+FA) or depleted of them (HSA-FA).

Sialic acid attenuates puromycin aminonucleoside-induced desialylation and oxidative stress in human podocytes.

Sialoglycoproteins make a significant contribution to the negative charge of the glomerular anionic glycocalyx-crucial for efficient functioning of the glomerular permselective barrier. Defects in sialylation have serious consequences on podocyte function leading to the development of proteinuria. The aim of the current study was to investigate potential mechanisms underlying puromycin aminonucleosisde (PAN)-induced desialylation and to ascertain whether they could be corrected by administration of free sialic acid.

Combined walking exercise and alkali therapy in patients with CKD4-5 regulates intramuscular free amino acid pools and ubiquitin E3 ligase expression.

Muscle-wasting in chronic kidney disease (CKD) arises from several factors including sedentary behaviour and metabolic acidosis. Exercise is potentially beneficial but might worsen acidosis through exercise-induced lactic acidosis. We studied the chronic effects of exercise in CKD stage 4-5 patients (brisk walking, 30 min, 5 times/week), and non-exercising controls; each group receiving standard oral bicarbonate (STD), or additional bicarbonate (XS) (Total n = 26; Exercising + STD n = 9; Exercising +XS n = 6; Control + STD n = 8; Control + XS n = 3).

Effect of angiotensin type 2 receptor over-expression on the rat mesangial cell fibrotic phenotype: effect of gender.

Background And Aim: The protective role of angiotensin type 2 receptors (AT2-Rs) is still controversial. As AT2-Rs are minimally expressed in adult tissues the aim of the current study was to over-express AT2-Rs in rat mesangial cells in order to ascertain their potential role in modulating renal scarring.

Methods: Male and female mesangial cells were transiently transfected with AT2-R or control vector then 'injured' with macrophage-conditioned medium (MCM).

Low-level C-reactive protein levels exert cytoprotective actions on human podocytes.

Background: Albuminuria and elevated C-reactive protein (CRP) levels are common manifestations of many inflammatory diseases. Cardiovascular-based drugs, with secondary anti-inflammatory actions, such as angiotensin-converting enzyme-inhibitors are able to reduce both proteinuria and CRP levels, raising the question of whether CRP directly influences the processes that result in proteinuria. As proteinuria is thought to be induced as a result of podocyte dysfunction, we investigated whether there is a pathomechanistic link with CRP.

Rat mesangial cells exhibit sex-specific profibrotic and proinflammatory phenotypes.

Background: Chronic renal disease progresses more rapidly in males compared to females. This study investigated whether there were any inherent differences between male and female mesangial cells that could contribute to this phenomenon and whether these differences could be modulated by sex hormones.

Methods: Experiments were carried out on cultured mesangial cells derived from adult male and female Wistar rat kidneys.

Perindoprilat modulates the activity of lipoprotein receptor-related protein in human mesangial cells.

Low density lipoprotein receptor-related protein (LRP) is a multifunctional endocytic receptor implicated in the modulation of a number of cellular processes, including the turnover of proteases and the degradation of extracellular matrix proteins. As such, it can play a key role in the control of fibrosis. The aim of this investigation was to ascertain whether the anti-fibrotic effects exerted by the angiotensin-converting enzyme inhibitor (ACE-I) perindoprilat on macrophage-conditioned medium (MPCM)-injured human mesangial cells can be modulated by this receptor.

Kallikrein gene 'knock-down' by small interfering RNA transfection induces a profibrotic phenotype in rat mesangial cells.

Background: Emerging evidence suggests that kallikrein exerts renoprotective effects independent of its haemodynamic actions. The aim of the current investigation was to delineate the role of kallikrein in the regulation of fibrosis, by 'knocking down' its expression using specific small interfering RNAs (siRNA).

Methods: Rat mesangial cells were treated with 12, 60, 120 nmol/l kallikrein-specific siRNAs.

Pharmacological enhancement of the kallikrein-kinin system promotes anti-fibrotic responses in human mesangial cells.

The aim of the present study was to investigate whether pharmacological enhancement of the renal kallikrein-kinin system using the vasopeptidase inhibitor omapatrilat plays a direct role in modulating the fibrotic responses of human mesangial cells to injury. Treatment with 40 micromol/L omapatrilat was able to reduce macrophage-conditioned medium (MPCM)-induced fibronectin levels without affecting mRNA expression. MPCM injury also suppressed kallikrein and low molecular weight kininogen mRNA.

Effects of mouse and human lipocalin homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin on gastrointestinal mucosal integrity and repair.

Background & Aims: The lipocalin superfamily, including the mouse and human homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin, show great functional diversity including roles in olfaction, transportation, and prostaglandin synthesis in mammals. Their potential role in maintaining gastrointestinal mucosal integrity and repair is, however, unclear.

Methods: Changes in 24p3/lcn2 expression in the mouse gut in response to various noxious agents were examined using Northern blot, in situ hybridization, and immunohistochemistry.

The role of the alpha-1 adrenoceptor in modulating human mesangial cell matrix production.

Background: The sympathetic nervous system is frequently activated in hypertension and may modify various aspects of renal function. Whether modulation of the sympathetic nervous system directly influences the development of renal fibrosis is yet to be established. The current study investigates the role of the alpha-1 adrenoceptor on human mesangial cell scarring.

Inflammation and caspase activation in long-term renal ischemia/reperfusion injury and immunosuppression in rats.

Background: We have previously shown the long-term influence of renal ischemia/reperfusion (I/R) injury and immunosuppression on fibrotic genes and apoptosis in a rat model. For the first time, we have now investigated the effects of I/R and immunosuppression on inflammation and caspase activation.

Methods: I/R injury was induced in the right kidney and the left was removed.

The role of bradykinin in the antifibrotic actions of perindoprilat on human mesangial cells.

Background: Angiotensin-converting enzyme inhibitors (ACE-I) protect against the development of glomerulosclerosis using mechanisms partly dissociated from their systemic antihypertensive action. The aim of the current study was to delineate the mechanism of action underlying the antifibrotic effects of the ACE-I perindoprilat in the context of macrophage-mediated scarring in human mesangial cells.

Methods: Mesangial cells were treated with macrophage-conditioned medium (MPCM) in the presence or absence of the ACE-I perindoprilat.

Acidosis downregulates leptin production from cultured adipocytes through a glucose transport-dependent post-transcriptional mechanism.

Metabolic acidosis, a common feature of uremia, has a well documented wasting effect on skeletal muscle. In contrast, the effect of metabolic acidosis on adipose tissue is unknown. Serum levels of the adipocyte hormone leptin have been shown to be lower in acidotic uremic rats when compared with uremic controls.