Sex differences in kidney metabolism may reflect sex-dependent outcomes in human diabetic kidney disease.

Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis, and greater injury when exposed to high glucose compared with PTECs from healthy females.

Urinary angiotensin-converting enzyme 2 and metabolomics in COVID-19-mediated kidney injury.

Background: Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the kidneys. Beyond serving as a crucial endogenous regulator of the renin-angiotensin system, ACE2 also possess a unique function to facilitate amino acid absorption. Our observational study sought to explore the relationship between urine ACE2 (uACE2) and renal outcomes in coronavirus disease 2019 (COVID-19).

Evaluation of novel glomerular filtration rate estimation equations in adolescents and young adults with type 1 diabetes.

Aims: Individuals with type 1 diabetes (T1D) are at an increased risk of chronic kidney disease making estimation of glomerular filtration rate (eGFR) an important component of diabetes care. Which eGFR equation is most appropriate to use in patients with T1D during the transition to adult care is unclear. We, therefore, sought to evaluate the performance of five eGFR equations in adolescents and young adults with T1D.

Follistatin-Like-1 (FSTL1) Is a Fibroblast-Derived Growth Factor That Contributes to Progression of Chronic Kidney Disease.

Our understanding of the mechanisms responsible for the progression of chronic kidney disease (CKD) is incomplete. Microarray analysis of kidneys at 4 and 7 weeks of age in mice, a model of progressive nephropathy characterized by proteinuria, interstitial fibrosis, and inflammation, revealed that Follistatin-like-1 () was one of only four genes significantly overexpressed at 4 weeks of age. mRNA levels for the receptors, and , increased in both mice and mice subjected to unilateral ureteral obstruction (UUO).

Recent Approaches to Targeting Canonical NFB Signaling in the Early Inflammatory Response to Renal IRI.

Ischemia reperfusion injury (IRI) is the most common cause of in-hospital AKI and is associated with increased morbidity and mortality. IRI is associated with an early phase of inflammation primarily regulated by the canonical NFB signaling pathway. Despite recent advances in our understanding of the pathogenesis of IRI, few therapeutic strategies have emerged.

Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study.

Background: Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of experimental kidney disease. ACE2 is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS). The relationship between sex and renal ACE2 expression in humans with kidney disease is a gap in current knowledge.

Inhibition of BRD4 Reduces Neutrophil Activation and Adhesion to the Vascular Endothelium Following Ischemia Reperfusion Injury.

Renal ischemia reperfusion injury (IRI) is associated with inflammation, including neutrophil infiltration that exacerbates the initial ischemic insult. The molecular pathways involved are poorly characterized and there is currently no treatment. We performed an in silico analysis demonstrating changes in NFκB-mediated gene expression in early renal IRI.

Kidney ACE2 expression: Implications for chronic kidney disease.

Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of chronic kidney disease (CKD) and is a membrane receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease (COVID-19), whereas transmembrane protease, serine 2 (TMPRSS2) is involved in viral attachment. Together, tissue expression of ACE2 and TMPRSS2 may determine infection. Sex, age, body mass index (BMI), and CKD are clinical risk factors for COVID-19 severity, but the relationships between kidney ACE2 and TMPRSS2 expression and these clinical variables are unknown.

Urinary proteomics links keratan sulfate degradation and lysosomal enzymes to early type 1 diabetes.

Diabetes is the leading cause of end-stage renal disease worldwide. Our understanding of the early kidney response to chronic hyperglycemia remains incomplete. To address this, we first investigated the urinary proteomes of otherwise healthy youths with and without type 1 diabetes and subsequently examined the enriched pathways that might be dysregulated in early disease using systems biology approaches.

Connectivity mapping of a chronic kidney disease progression signature identified lysine deacetylases as novel therapeutic targets.

Tubulointerstitial injury is an important determinant of chronic kidney disease progression, yet treatment is limited. Accordingly, we derived a chronic kidney disease progression signature based on aging and disease in Col4a3 mice, a model associated with proteinuria and progressive loss of kidney function. Computational drug repurposing with the Connectivity Map identified vorinostat, a lysine deacetylase inhibitor, as a candidate treatment to reverse progression signature gene expression.

Angiotensin-[1-7] attenuates kidney injury in experimental Alport syndrome.

Angiotensin-[1-7] (Ang-[1-7]) antagonize the actions of the renin-angiotensin-system via the Mas receptor and thereby exert renoprotective effects. Murine recombinant angiotensin-converting enzyme (ACE)2 was reported to show renoprotective effects in an experimental Alport syndrome model; however, the protective effect of direct administration of Ang-[1-7] is unknown. Here, we used Col4a3 mice as a model of Alport syndrome, which were treated with saline or Ang- [1-7]; saline-treated wild-type mice were used as a control group.

Peptidomic Analysis of Urine from Youths with Early Type 1 Diabetes Reveals Novel Bioactivity of Uromodulin Peptides .

Chronic hyperglycemia is known to disrupt the proteolytic milieu, initiating compensatory and maladaptive pathways in the diabetic kidney. Such changes in intrarenal proteolysis are captured by the urinary peptidome. To elucidate the early kidney response to chronic hyperglycemia, we conducted a peptidomic investigation into urines from otherwise healthy youths with type 1 diabetes and their non-diabetic peers using unbiased and targeted mass spectrometry-based techniques.

Rethinking Lupus Nephritis Classification on a Molecular Level.

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) lupus nephritis (LN) classification is under reconsideration, given challenges with inter-rater reliability and resultant inconsistent relationship with treatment response. Integration of molecular classifiers into histologic evaluation can improve diagnostic precision and identify therapeutic targets. This study described the relationship between histological and molecular phenotypes and clinical responses in LN.

Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ.

Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin-angiotensin system (RAS) and transforming growth factor β (TGFβ) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in mice by olmesartan treatment.

B-Cell Deficiency Lowers Blood Pressure in Mice.

The proto-oncogene c-myb (and corresponding nuclear transcription factor, c-Myb) regulates the proliferation and differentiation of hematologic and vascular smooth muscle cells; however, the role of c-Myb in blood pressure regulation is unknown. Here, we show that mice homozygous for a hypomorphic c-myb allele ( c-myb ) conferring reduced c-Myb activity manifest reduced peripheral blood and kidney B220 B-cells and have decreased systolic (104±2 versus 120±1 mm Hg; P<0.0001) and diastolic blood pressure (71±2 versus 83±1 mm Hg; P<0.

Social Determinants of Health Are Associated with Markers of Renal Injury in Adolescents with Type 1 Diabetes.

Objective: To examine the relationship between the social determinants of health and markers of early renal injury in adolescent patients with type 1 diabetes (T1D).

Study Design: Renal outcomes included estimated glomerular filtration rate (eGFR) and albumin-creatinine excretion ratio (ACR). Differences in urinary and serum inflammatory markers also were assessed in relation to social determinants of health.

Nrf2 Deficiency Upregulates Intrarenal Angiotensin-Converting Enzyme-2 and Angiotensin 1-7 Receptor Expression and Attenuates Hypertension and Nephropathy in Diabetic Mice.

We investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout mice and Akita mice treated with trigonelline (an Nrf2 inhibitor) or oltipraz (an Nrf2 activator). We also examined rat immortalized RPTCs (IRPTCs) stably transfected with control plasmids or plasmids containing rat angiotensinogen (Agt), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (Ace2), or angiotensin 1-7 (Ang 1-7) receptor (MasR) gene promoters.

Angiotensin-converting enzyme 2 and renal disease.

Purpose Of Review: The renin-angiotensin system (RAS) is a pivotal player in the physiology and pathophysiology of cardiovascular and renal systems. Discovery of angiotensin-converting enzyme 2 (ACE2), capable of cleaving RAS effector peptide angiotensin (Ang) II into biologically active Ang-(1-7), has increased the complexity of our knowledge of the RAS. ACE2 expression is abundant in the kidney and is thought to provide protection against injury.

Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome.

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase in the renin-angiotensin system that catalyzes the breakdown of angiotensin II to angiotensin 1-7. We have reported that ACE2 expression in the kidney is reduced in experimental Alport syndrome but the impact of this finding on disease progression has not been studied. Accordingly, we evaluated effects of murine recombinant ACE2 treatment in Col4a3 knockout mice, a model of Alport syndrome characterized by proteinuria and progressive renal injury.

Insights into Diabetic Kidney Disease Using Urinary Proteomics and Bioinformatics.

A number of proteomic and peptidomic analyses of urine from diabetic subjects have been published in the quest for a biomarker that predicts progression of nephropathy. Less attention has been paid to the relationships between urinary proteins and the underlying biological processes revealed by the analyses. In this review, we focus on the biological processes identified by studying urinary proteins and protein-protein interactions at each stage of diabetic nephropathy to provide an overview of the events underlying progression of kidney disease reflected in the urine.

Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease.

Male sex predisposes to many kidney diseases. Considering that androgens exert deleterious effects in a variety of cell types within the kidney, we hypothesized that dihydrotestosterone (DHT) would alter the biology of the renal tubular cell by inducing changes in the proteome. We employed stable isotope labeling with amino acids (SILAC) in an indirect spike-in fashion to accurately quantify the proteome in DHT- and 17β-estradiol (EST)-treated human proximal tubular epithelial cells (PTEC).

Influence of sex on hyperfiltration in patients with uncomplicated type 1 diabetes.

The aim of this analysis was to examine sex-based differences in renal segmental resistances in healthy controls (HCs) and patients with type 1 diabetes (T1D). We hypothesized that hyperfiltration-an early hemodynamic abnormality associated with diabetic nephropathy-would disproportionately affect women with T1D, thereby attenuating protection against the development of renal complications. Glomerular hemodynamic parameters were evaluated in HC ( = 30) and in normotensive, normoalbuminuric patients with T1D and either baseline normofiltration [ = 36, T1D-N, glomerular filtration rate (GFR) 90-134 ml·min·1.

Assessment of urinary microparticles in normotensive patients with type 1 diabetes.

Aims/hypothesis: Assessment of urinary extracellular vesicles including exosomes and microparticles (MPs) is an emerging approach for non-invasive detection of renal injury. We have previously reported that podocyte-derived MPs are increased in diabetic mice in advance of albuminuria. Here, we hypothesised that type 1 diabetes and acute hyperglycaemia would increase urinary podocyte MP levels in uncomplicated diabetes.