DACH1 as a multifaceted and potentially druggable susceptibility factor for kidney disease

Kidney diseases affect more than 15% of adults in the US, yet drug development in the kidney field, when compared with that for other common diseases, has been lagging behind. Modifiers that increase the susceptibility to injury and contribute to the pathogenesis and progression of kidney disease include genetic and environmental factors and epigenetic mechanisms. In this issue of the JCI, Cao et al. and Doke et al. independently report the identification of a susceptibility factor called Dachshund homolog 1 (DACH1). Both groups identify an association of reduced DACH1 expression with kidney disease, using different screening approaches, studying different types of human kidney diseases, and using different experimental models, making the fact that both stumbled over the same protein very compelling. Combined, these studies highlight DACH1 as a key safeguard in the kidney, granting various cell types proper function by modulating several molecular pathways

Lipid Metabolism Gets in a JAML during Kidney Disease

It is still unclear if the ability of key regulators of actin cytoskeletal remodeling to influence lipid metabolism contributes to kidney injury. In this issue of Cell Metabolism, Fu et al. (2020) show that junctional adhesion molecule-like (JAML) is a novel mediator of glomerular disease progression while suggesting a direct link between defects in cell adhesion and lipotoxicity

Podocyte Pathology and Nephropathy – Sphingolipids in Glomerular Diseases

Sphingolipids are components of the lipid rafts in plasma membranes, which are important for proper function of podocytes, a key element of the glomerular filtration barrier. Research revealed an essential role of sphingolipids and sphingolipid metabolites in glomerular disorders of genetic and non-genetic origin. The discovery that glucocerebrosides accumulate in Gaucher disease in glomerular cells and are associated with clinical proteinuria initiated intensive research into the function of other sphingolipids in glomerular disorders. The accumulation of sphingolipids in other genetic diseases including Tay–Sachs, Sandhoff, Fabry, hereditary inclusion body myopathy 2, Niemann–Pick, and nephrotic syndrome of the Finnish type and its implications with respect to glomerular pathology will be discussed. Similarly, sphingolipid accumulation occurs in glomerular diseases of non-genetic origin including diabetic kidney disease (DKD), HIV-associated nephropathy, focal segmental glomerulosclerosis (FSGS), and lupus nephritis. Sphingomyelin metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate have also gained tremendous interest. We recently described that sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is expressed in podocytes where it modulates acid sphingomyelinase activity and acts as a master modulator of danger signaling. Decreased SMPDL3b expression in post-reperfusion kidney biopsies from transplant recipients with idiopathic FSGS correlates with the recurrence of proteinuria in patients and in experimental models of xenotransplantation. Increased SMPDL3b expression is associated with DKD. The consequences of differential SMPDL3b expression in podocytes in these diseases with respect to their pathogenesis will be discussed. Finally, the role of sphingolipids in the formation of lipid rafts in podocytes and their contribution to the maintenance of a functional slit diaphragm in the glomerulus will be discussed

Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease

Chronic kidney disease (CKD) is a global health problem with rising incidence and prevalence. Among several pathogenetic mechanisms responsible for disease progression, lipid accumulation in the kidney parenchyma might drive inflammation and fibrosis, as has been described in fatty liver diseases. Lipids and their metabolites have several important structural and functional roles, as they are constituents of cell and organelle membranes, serve as signalling molecules and are used for energy production. However, although lipids can be stored in lipid droplets to maintain lipid homeostasis, lipid accumulation can become pathogenic. Understanding the mechanisms linking kidney parenchymal lipid accumulation to CKD of metabolic or non-metabolic origin is challenging, owing to the tremendous variety of lipid species and their functional diversity across different parenchymal cells. Nonetheless, multiple research reports have begun to emphasize the effect of dysregulated kidney lipid metabolism in CKD progression. For example, altered cholesterol and fatty acid metabolism contribute to glomerular and tubular cell injury. Newly developed lipid-targeting agents are being tested in clinical trials in CKD, raising expectations for further therapeutic development in this field

Podocytopathy in Diabetes: A Metabolic Disorder

Background: Despite multifactorial interventions, the prevalence of diabetic kidney disease (DKD) is reaching epidemic proportions worldwide. Loss of podocytes, the cells forming the glomerular filtration barrier, occurs early in the development of DKD and is associated with the presence of albuminuria. Summary: Recent studies have implicated circulating hormones, adipokines and lipids in the development and progression of DKD. Key Message: Although the endocrine effects of these factors are widely recognized, less is known about their direct effects on podocytes and the resulting implications for DKD

Mechanisms and Implications of Podocyte Autophagy in Chronic Kidney Disease

Autophagy is a protective mechanism through which cells degrade and recycle proteins and organelles to maintain cellular homeostasis and integrity. An accumulating body of evidence underscores the significant impact of dysregulated autophagy on podocyte injury in chronic kidney disease. In this review, we provide a comprehensive overview of the diverse types of autophagy and their regulation in cellular homeostasis, with a specific emphasis on podocytes. Furthermore, we discuss recent findings that focus on the functional role of different types of autophagy during podocyte injury in chronic kidney disease. The intricate interplay between different types of autophagy and podocyte health requires further research, which is critical for understanding the pathogenesis of CKD and developing targeted therapeutic interventions