Resazurin dye is an in vivo sensor of kidney tubular function.

Glomerular filtration rate (GFR) is the main functional index of kidney health and disease. Currently, no methods are available to directly measure tubular mass and function. Here, we report a serendipitous finding that the in vitro cell viability dye resazurin can be used in mice as an exogenous sensor of tubular function.

Induction of Plasmalemmal vesicle-associated protein exacerbates glomerular endothelial injury in thrombotic microangiopathy.

Glomerular endothelial cell (GEnC) injury is a common feature across the wide spectrum of glomerular diseases. We recently reported that the endothelial-specific knockout of increases the susceptibility to GEnC injury and subsequent development of subacute thrombotic microangiopathy (TMA). However, the mechanism(s) mediating GEnCs response to injury in TMA are poorly understood.

Activation of branched chain amino acid catabolism protects against nephrotoxic acute kidney injury.

Acute kidney injury (AKI) is a major risk factor for chronic kidney disease (CKD), and there are currently no therapies for AKI. Proximal tubules (PTs) are particularly susceptible to AKI, due to nephrotoxins such as aristolochic acid I (AAI). Normal PTs use fatty acid oxidation and branched chain amino acid (BCAA; valine, leucine, and isoleucine) catabolism to generate ATP; however, in AKI, these pathways are downregulated.

Targeting KLF2 as a Novel Therapy for Glomerular Endothelial Cell Injury in Diabetic Kidney Disease.

Background: DKD is a microvascular disease, and glomerular endothelial cell injury is a key pathological event in DKD development. Through unbiased screening of glomerular transcriptomes, we previously identified KLF2 as a highly regulated gene in diabetic kidneys. KLF2 exhibits protective effects in endothelial cells by inhibiting inflammation, thrombotic activation, and angiogenesis, all of which are protective for cardiovascular disease.

Podocyte-specific KLF6 primes proximal tubule CaMK1D signaling to attenuate diabetic kidney disease.

Diabetic kidney disease (DKD) is the main cause of chronic kidney disease worldwide. While injury to the podocytes, visceral epithelial cells that comprise the glomerular filtration barrier, drives albuminuria, proximal tubule (PT) dysfunction is the critical mediator of DKD progression. Here, we report that the podocyte-specific induction of human KLF6, a zinc-finger binding transcription factor, attenuates podocyte loss, PT dysfunction, and eventual interstitial fibrosis in a male murine model of DKD.

A Small Molecule Agonist of Krüppel-Like Factor 15 in Proteinuric Kidney Disease.

Key Points: A human podocyte-based high-throughput screen identified a novel agonist of Krüppel-like factor 15 (BT503), independent of glucocorticoid signaling. BT503 demonstrated renoprotective effects in three independent proteinuric kidney murine models. BT503 directly binds to inhibitor of nuclear factor kappa-B kinase subunit beta to inhibit NF-κB activation, which, subsequently restores Krüppel-like factor 15 under cell stress.

Central role of podocytes in mediating cellular cross talk in glomerular health and disease.

Podocytes are highly specialized epithelial cells that surround the capillaries of the glomeruli in the kidney. Together with the glomerular endothelial cells, these postmitotic cells are responsible for regulating filtrate from the circulating blood with their organized network of interdigitating foot processes that wrap around the glomerular basement membrane. Although podocyte injury and subsequent loss is the hallmark of many glomerular diseases, recent evidence suggests that the cell-cell communication between podocytes and other glomerular and nonglomerular cells is critical for the development and progression of kidney disease.

The loss of profilin1 is catastrophic to podocytes.

Profilin1 belongs to a family of small monomeric actin-binding proteins with diverse roles in fundamental actin-dependent cellular processes required for cell survival. Podocytes are postmitotic visceral epithelial cells critical for the structure and function of the kidney filtration barrier. There is emerging evidence that the actin-related mode of cell death known as mitotic catastrophe is an important pathway involved in podocyte loss.

Dialysis resource allocation in critical care: the impact of the COVID-19 pandemic and the promise of big data analytics.

The COVID-19 pandemic resulted in an unprecedented burden on intensive care units (ICUs). With increased demands and limited supply, critical care resources, including dialysis machines, became scarce, leading to the undertaking of value-based cost-effectiveness analyses and the rationing of resources to deliver patient care of the highest quality. A high proportion of COVID-19 patients admitted to the ICU required dialysis, resulting in a major burden on resources such as dialysis machines, nursing staff, technicians, and consumables such as dialysis filters and solutions and anticoagulation medications.

Endotoxemia Correlates with Kidney Function and Length of Stay in Critically Ill Patients.

Introduction: Endotoxin is a key driver of sepsis, which frequently causes acute kidney injury (AKI). However, endotoxins may also be found in non-bacteremic critically ill patients, likely from intestinal translocation. Preclinical models show that endotoxins can directly injure the kidneys, and in COVID-19 patients, endotoxemia correlated with AKI.

Single-Cell Spatial MIST for Versatile, Scalable Detection of Protein Markers.

High-multiplex detection of protein biomarkers across tissue regions has been an attractive spatial biology approach due to significant advantages over traditional immunohistochemistry (IHC) methods. Different from most methods, spatial multiplex in situ tagging (MIST) transfers the spatial protein expression information to an ultrahigh-density, large-scale MIST array. This technique has been optimized to reach single-cell resolution by adoption of smaller array units and 30% 8-arm PEG polymer as transfer medium.

Geographic and Temporal Trends in COVID-Associated Acute Kidney Injury in the National COVID Cohort Collaborative.

Background: AKI is associated with mortality in patients hospitalized with coronavirus disease 2019 (COVID-19); however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied.

Methods: Electronic health record data were obtained from 53 health systems in the United States in the National COVID Cohort Collaborative. We selected hospitalized adults diagnosed with COVID-19 between March 6, 2020, and January 6, 2022.

Podocyte-Parietal Epithelial Cell Interdependence in Glomerular Development and Disease.

Podocytes and parietal epithelial cells (PECs) are among the few principal cell types within the kidney glomerulus, the former serving as a crucial constituent of the kidney filtration barrier and the latter representing a supporting epithelial layer that adorns the inner wall of Bowman's capsule. Podocytes and PECs share a circumscript developmental lineage that only begins to diverge during the S-shaped body stage of nephron formation-occurring immediately before the emergence of the fully mature nephron. These two cell types, therefore, share a highly conserved gene expression program, evidenced by recently discovered intermediate cell types occupying a distinct spatiotemporal gene expression zone between podocytes and PECs.

Electromyogram-Based Lip-Reading via Unobtrusive Dry Electrodes and Machine Learning Methods.

Lip-reading provides an effective speech communication interface for people with voice disorders and for intuitive human-machine interactions. Existing systems are generally challenged by bulkiness, obtrusiveness, and poor robustness against environmental interferences. The lack of a truly natural and unobtrusive system for converting lip movements to speech precludes the continuous use and wide-scale deployment of such devices.

Transcriptional regulation of proximal tubular metabolism in acute kidney injury.

The kidney, and in particular the proximal tubule (PT), has a high demand for ATP, due to its function in bulk reabsorption of solutes. In normal PT, ATP levels are predominantly maintained by fatty acid β-oxidation (FAO), the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. The normal PT also undertakes gluconeogenesis and metabolism of amino acids.

COVID-19-associated AKI in hospitalized US patients: incidence, temporal trends, geographical distribution, risk factors and mortality.

Background: Acute kidney injury (AKI) is associated with mortality in patients hospitalized with COVID-19, however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied.

Methods: Electronic health record data were obtained from 53 health systems in the United States (US) in the National COVID Cohort Collaborative (N3C). We selected hospitalized adults diagnosed with COVID-19 between March 6th, 2020, and January 6th, 2022.

Endothelial-specific loss of Krüppel-Like Factor 4 triggers complement-mediated endothelial injury.

Thrombotic microangiopathy (TMA) in the kidney represents the most severe manifestation of kidney microvascular endothelial injury. Despite the source of the inciting event, the diverse clinical forms of kidney TMA share dysregulation of endothelial cell transcripts and complement activation. Here, we show that endothelial-specific knockdown of Krüppel-Like Factor 4 (Klf4), an anti-inflammatory and antithrombotic zinc-finger transcription factor, increases the susceptibility to glomerular endothelial injury and microangiopathy in two genetic murine models that included endothelial nitric oxide synthase knockout mice and aged mice (52 weeks), as well as in a pharmacologic model of TMA using Shiga-toxin 2.

Short- and Long-Term Recovery after Moderate/Severe AKI in Patients with and without COVID-19.

Background: Severe AKI is strongly associated with poor outcomes in coronavirus disease 2019 (COVID-19), but data on renal recovery are lacking.

Methods: We retrospectively analyzed these associations in 3299 hospitalized patients (1338 with COVID-19 and 1961 with acute respiratory illness but who tested negative for COVID-19). Uni- and multivariable analyses were used to study mortality and recovery after Kidney Disease Improving Global Outcomes Stages 2 and 3 AKI (AKI-2/3), and Machine Learning was used to predict AKI and recovery using admission data.

Loss of Functional SCO2 Attenuates Oxidative Stress in Diabetic Kidney Disease.

Increased oxidative stress in glomerular endothelial cells (GEnCs) contributes to early diabetic kidney disease (DKD). While mitochondrial respiratory complex IV activity is reduced in DKD, it remains unclear whether this is a driver or a consequence of oxidative stress in GEnCs. Synthesis of cytochrome C oxidase 2 (SCO2), a key metallochaperone in the electron transport chain, is critical to the biogenesis and assembly of subunits required for functional respiratory complex IV activity.

Recent Advances in Kidney Bioengineering.

Kidney disease is an epidemic that affects more than 600 million people worldwide. The socioeconomic impacts of the disease disproportionately affect Hispanic and non-Hispanic Black Americans, making the disease an issue of social inequality. The urgency of this situation has only become worse during the COVID-19 pandemic, as those who are hospitalized for COVID-19 have an increased risk of kidney failure.

Loss of Functional SCO2 Attenuates Oxidative Stress in Diabetic Kidney Disease.

Increased oxidative stress in glomerular endothelial cells (GEnCs) contributes to early diabetic kidney disease (DKD). While mitochondrial respiratory complex IV activity is reduced in DKD, it remains unclear whether this is a driver or a consequence of oxidative stress in GEnCs. Synthesis of cytochrome C oxidase 2 (SCO2), a key metallochaperone in the electron transport chain, is critical to the biogenesis and assembly of subunits required for functional respiratory complex IV activity.

Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation.

Loss of fatty acid β-oxidation (FAO) in the proximal tubule is a critical mediator of acute kidney injury and eventual fibrosis. However, transcriptional mediators of FAO in proximal tubule injury remain understudied. Krüppel-like factor 15 (KLF15), a highly enriched zinc-finger transcription factor in the proximal tubule, was significantly reduced in proximal tubule cells after aristolochic acid I (AAI) treatment, a proximal tubule-specific injury model.

Podocyte-specific KLF4 is required to maintain parietal epithelial cell quiescence in the kidney.

Podocyte loss triggering aberrant activation and proliferation of parietal epithelial cells (PECs) is a central pathogenic event in proliferative glomerulopathies. Podocyte-specific Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor, is essential for maintaining podocyte homeostasis and PEC quiescence. Using mice with podocyte-specific knockdown of Klf4, we conducted glomerular RNA-sequencing, tandem mass spectrometry, and single-nucleus RNA-sequencing to identify cell-specific transcriptional changes that trigger PEC activation due to podocyte loss.