LILRB3 genetic variation is associated with kidney transplant failure in African American recipients.

African American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared with other racial and ethnic populations, highlighting the need to identify causative factors. Here, in the Genomics of Chronic Allograft Rejection cohort, pretransplant blood RNA sequencing revealed a cluster of four consecutive missense single-nucelotide polymorphisms (SNPs), within the leukocyte immunoglobulin-like receptor B3 (LILRB3) gene, strongly associated with death-censored graft loss. This SNP cluster (named LILRB3-4SNPs) encodes missense mutations at amino acids 617-618 proximal to a SHP1/2 phosphatase-binding immunoreceptor tyrosine-based inhibitory motif.

Modulation of TGF-β signaling new approaches toward kidney disease and fibrosis therapy.

The prevalence of chronic kidney disease (CKD) is increasing worldwide, posing a significant healthcare challenge. Despite the immense burden of CKD, optimal therapies remain limited in impact. Kidney fibrosis is a common mediator of all CKD progression, characterized by excessive extracellular matrix deposition and scarring of kidney parenchyma.

Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV2 Infection.

Background: Acute kidney injury (AKI) is common in SARS-CoV-2 infection and COVID-19, often leading to long-term kidney dysfunction. However, the transcriptomic features of AKI severity and its long-term effects are underexplored.

Methods: We performed bulk RNA sequencing on peripheral blood mononuclear cells (PBMCs) from hospitalized SARS-CoV-2 patients and complemented these findings with proteomic data from the same cohort.

Relationship between Podocyte Injury and Renal Outcomes in Patients with Acute Kidney Injury: A Report from a Retrospective Study in China.

Introduction: Podocyte injury has been proven to be a major cause for poor renal outcomes after acute kidney injury (AKI). However, clinical trial data are still limited. This study aimed to explore the clinical correlations between podocyte injury and renal outcomes in hospitalized AKI patients.

RTN1A mediates diabetes-induced AKI-to-CKD transition.

Diabetic patients have increased susceptibility to acute kidney injury (AKI), and AKI could progress to chronic tubulointerstitial injury and fibrosis, referred to as AKI-to-chronic kidney disease (AKI-to-CKD) transition. However, whether diabetes directly promotes AKI-to-CKD transition is not known. We previously showed that reticulon-1A (RTN1A), a gene highly upregulated in injured renal tubular epithelial cells (RTECs), promotes AKI-to-CKD transition in nondiabetic settings.

Navigating the Global Economic Landscape of Dialysis: A Summary of Expert Opinions from The 4th International Congress of Chinese Nephrologists.

Background: Chronic kidney disease (CKD) continues to be a significant global public health issue. The escalating burden of CKD is probably driven by the aging population and the rising prevalence of diabetes. CKD not only adversely impacts an individual's health and well-being, but also poses significant challenge on the economy of the society.

Role and Mechanisms of Tyro3 in Podocyte Biology and Glomerular Disease.

Background: Podocyte loss occurs in both primary and secondary glomerular diseases, leading to the progression of kidney disease. A large body of evidence suggests that apoptosis and detachment are the mechanisms mediating the reduction in podocyte numbers in glomerular diseases. Recent studies demonstrate a renal protective effect of protein S (PS) through the activation of Tyro3, one of the TAM receptors.

A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury.

Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. Herein, aristolochic acid nephropathy (AAN) and folic acid nephropathy (FAN) models were used to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1, myeloid cell-specific, and kidney tubule-specific C5ar1 knockout mice.

Perirenal fat and chronic kidney disease in type 2 diabetes: The mediation role of afferent arteriolar resistance.

Aim: Perirenal fat (PRF) is an independent predictor for chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) patients. Previous studies speculated that PRF may promote renal dysfunction through affecting renal hemodynamics. To verify this hypothesis, we studied the relationship between PRF and renal hemodynamics in T2DM.

Targeting Krüppel-Like Factor 2 as a Novel Therapy for Glomerular Endothelial Cell Injury in Diabetic Kidney Disease.

Key Points: Krüppel-like factor 2 (KLF2) has emerged as a key endoprotective regulator by suppressing inflammatory and oxidative pathways, thrombotic activation, and angiogenesis. Our study now demonstrates that KLF2 protects against glomerular endothelial injury and attenuates diabetic kidney disease progression in mice. Compound 6 is a novel KLF2 activator that can potentially confer dual cardiorenal protection against diabetic complications.

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.

Single-Nucleus RNA Sequencing Reveals Loss of Distal Convoluted Tubule 1 Renal Tubules in HIV Viral Protein R Transgenic Mice.

Although hyponatremia and salt wasting are common in patients with HIV/AIDS, the understanding of their contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the Slc12a3 gene, encoding the sodium-chloride cotransporter (which is responsible for sodium reabsorption in distal nephron segments), single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr transgenic (Vpr Tg) mice.

Krüppel-like factor 2 is an endoprotective transcription factor in diabetic kidney disease.

Diabetic kidney disease (DKD) is a microvascular complication of diabetes, and glomerular endothelial cell (GEC) dysfunction is a key driver of DKD pathogenesis. Krüppel-like factor 2 (KLF2), a shear stress-induced transcription factor, is among the highly regulated genes in early DKD. In the kidney, KLF2 expression is mostly restricted to endothelial cells, but its expression is also found in immune cell subsets.

LRG1 loss effectively restrains glomerular TGF-β signaling to attenuate diabetic kidney disease.

Transforming growth factor (TGF)-β signaling is a well-established pathogenic mediator of diabetic kidney disease (DKD). However, owing to its pleiotropic actions, its systemic blockade is not therapeutically optimal. The expression of TGF-β signaling regulators can substantially influence TGF-β's effects in a cell- or context-specific manner.

Molecular mechanism of renal lipid accumulation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression.

Cholesterol 25-Hydroxylase Protects Against Diabetic Kidney Disease by Regulating ADP Ribosylation Factor 4.

Cholesterol 25-hydroxylase (CH25H), an enzyme involved in cholesterol metabolism, regulates inflammatory responses and lipid metabolism. However, its role in kidney disease is not known.  The author found that CH25H transcript is expressed mostly in glomerular and peritubular endothelial cells and that its expression increased in human and mouse diabetic kidneys.

Podocyte-targeted therapies - progress and future directions.

Podocytes are the key target cells for injury across the spectrum of primary and secondary proteinuric kidney disorders, which account for up to 90% of cases of kidney failure worldwide. Seminal experimental and clinical studies have established a causative link between podocyte depletion and the magnitude of proteinuria in progressive glomerular disease. However, no substantial advances have been made in glomerular disease therapies, and the standard of care for podocytopathies relies on repurposed immunosuppressive drugs.

Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis.

Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes.

Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury.

Retinoic acid receptor responder protein-1 (RARRES1) is a podocyte-enriched transmembrane protein whose increased expression correlates with human glomerular disease progression. RARRES1 promotes podocytopenia and glomerulosclerosis via p53-mediated podocyte apoptosis. Importantly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble protein (sRARRES1) and subsequent podocyte uptake by endocytosis, as a cleavage mutant RARRES1 exerted no effects in vitro or in vivo.

Integrated multiomics implicates dysregulation of ECM and cell adhesion pathways as drivers of severe COVID-associated kidney injury.

COVID-19 has been a significant public health concern for the last four years; however, little is known about the mechanisms that lead to severe COVID-associated kidney injury. In this multicenter study, we combined quantitative deep urinary proteomics and machine learning to predict severe acute outcomes in hospitalized COVID-19 patients. Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrated predictive power for both discovery and validation set with 87% and 79% accuracy, respectively.

HIPK2 C-terminal domain inhibits NF-κB signaling and renal inflammation in kidney injury.

HIPK2 is a multifunctional kinase that acts as a key pathogenic mediator of chronic kidney disease and fibrosis. It acts as a central effector of multiple signaling pathways implicated in kidney injury, such as TGF-β/Smad3-mediated extracellular matrix accumulation, NF-κB-mediated inflammation, and p53-mediated apoptosis. Thus, a better understanding of the specific HIPK2 regions necessary for distinct downstream pathway activation is critical for optimal drug development for CKD.