"Idiopathic" minimal change nephrotic syndrome: a podocyte mystery nears the end.

The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of induce a hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα.

Cytokine storm-based mechanisms for extrapulmonary manifestations of SARS-CoV-2 infection.

Viral illnesses like SARS-CoV-2 have pathologic effects on nonrespiratory organs in the absence of direct viral infection. We injected mice with cocktails of rodent equivalents of human cytokine storms resulting from SARS-CoV-2/COVID-19 or rhinovirus common cold infection. At low doses, COVID-19 cocktails induced glomerular injury and albuminuria in zinc fingers and homeoboxes 2 (Zhx2) hypomorph and Zhx2+/+ mice to mimic COVID-19-related proteinuria.

Secretion of the epithelial sodium channel chaperone PCSK9 from the cortical collecting duct links sodium retention with hypercholesterolemia in nephrotic syndrome.

The proprotein PCSK9 functions as a chaperone for the epithelial sodium channel in the cortical collecting duct (CCD), is highly expressed in the liver, and plays a significant role in the pathogenesis of hypercholesterolemia. Lower levels of PCSK9 expression also occur in the normal kidney and intestine. Here, we found increased PCSK9 expression in the CCD of biopsies of patients with primary glomerular disease and explored a possible relationship with hypercholesterolemia of nephrotic syndrome.

The zinc fingers and homeoboxes 2 protein ZHX2 and its interacting proteins regulate upstream pathways in podocyte diseases.

Zinc fingers and homeoboxes (ZHX) proteins are heterodimeric transcriptional factors largely expressed at the cell membrane in podocytes in vivo. We found ZHX2-based heterodimers in podocytes, with ZHX2-ZHX1 predominantly at the cell membrane of the podocyte cell body, and ZHX2-ZHX3 at the slit diaphragm. In addition to changes in overall ZHX2 expression, there was increased podocyte nuclear ZHX3 and ZHX2 in patients with focal segmental glomerulosclerosis, and increased podocyte nuclear ZHX1 in patients with minimal change disease.

[ManNAc, a new therapeutic agent to reduce Angptl4-induced proteinuria in MCD].

Current therapies used in minimal change disease (MCD) were originally designed to cure other diseases. They are only partially efficient, and present inconvenient side effects. Therefore, understanding the molecular mechanisms implicated in the pathogenesis of proteinuria in MCD could lead to new therapeutic strategies.

Novel therapeutic approaches for chronic kidney disease due to glomerular disorders.

Improved understanding of glomerular disease mechanisms over the past decade has led to the emergence of new and targeted therapeutic strategies for chronic kidney disease (CKD). Most promising among these are the administration of recombinant mutated human angiopoietin-like 4, sialic acid-related sugars that induce sialylation in vivo, compounds related to Bis-T-23, and immune depletion of the soluble urokinase receptor from the circulation. Taking these therapeutic strategies into clinical trials will be the first step away from repurposed and relatively toxic drugs currently used for treating kidney disease.

The proteinuria-hypertriglyceridemia connection as a basis for novel therapeutics for nephrotic syndrome.

The development of new and specific treatment options for kidney disease in general and glomerular diseases in specific has lagged behind other fields like heart disease and cancer. As a result, nephrologists have had to test and adapt therapeutics developed for other indications to treat glomerular diseases. One of the major factors contributing to this inertia has been the poor understanding of disease mechanisms.

Angiopoietin-like 4 based therapeutics for proteinuria and kidney disease.

Current drugs used to treat proteinuric disorders of the kidney have been borrowed from other branches of medicine, and are only partially effective. The discovery of a central, mechanistic role played by two different forms of the secreted glycoprotein angiopoietin-like 4 (Angptl4) in human and experimental glomerular disease has opened new treatment avenues. Localized upregulation of a hyposialylated form (lacks sialic acid residues) of Angptl4 secreted by podocytes induces the cardinal morphological and clinical manifestations of human minimal change disease, and is also being increasingly recognized as a significant contributor toward proteinuria in experimental diabetic nephropathy.

Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome.

The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein.

Telomerase at the center of collapsing glomerulopathy.

Collapsing glomerulopathy, the classic kidney lesion in HIV-associated nephropathy, is characterized by the closure of glomerular capillary loops and epithelial cell proliferation. A new study shows that upregulation of TERT, the reverse transcriptase component of telomerase, in podocytes, the key filtration cells in the kidney, plays a major part in the development of this condition by activating Wnt signaling (pages 111–119).

New insights into human minimal change disease: lessons from animal models.

The pathogenesis of minimal change disease (MCD), considered to be the simplest form of nephrotic syndrome, has been one of the major unsolved mysteries in kidney disease. In this review, recent landmark studies that have led to the unraveling of MCD are discussed. A recent study now explains the molecular basis of major clinical and morphologic changes in MCD.

Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome.

The main manifestations of nephrotic syndrome include proteinuria, hypoalbuminemia, edema, hyperlipidemia and lipiduria. Common causes of nephrotic syndrome are diabetic nephropathy, minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) and membranous nephropathy. Among the primary glomerular diseases, MCD is usually sensitive to glucocorticoid treatment, whereas the other diseases show variable responses.

ZHX proteins regulate podocyte gene expression during the development of nephrotic syndrome.

Transcriptional regulation of podocyte gene expression in primary glomerular disease is poorly understood. In this study, we demonstrate a prominent role of members of the ZHX (zinc fingers and homeoboxes) family of proteins in regulating podocyte gene expression during the development of nephrotic syndrome. While studying mechanisms of glomerular disease, rat ZHX3 was cloned from a down-regulated gene fragment; its cellular localization, DNA binding, and transcriptional repressor properties were characterized; and its ability to influence podocyte gene expression directly or via ZHX1 and ZHX2 was studied.

New insights into the fatty acid-binding protein (FABP) family in the small intestine.

The fatty acid-binding protein (FABP) superfamily is constituted by 14-15 kDa soluble proteins which bind with a high affinity either long-chain fatty acids (LCFAs), bile acids (BAs) or retinoids. In the small intestine, three different FABP isoforms exhibiting a high affinity for LCFAs and/or BAs are expressed: the intestinal and the liver-type (I-FABP and L-FABP) and the ileal bile acid-binding protein (I-BABP). Despite of extensive investigations, their respective physiological function(s) are not clearly established.

Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse.

Conjugated linoleic acids (CLA) are a class of positional, geometric, conjugated dienoic isomers of linoleic acid (LA). Dietary CLA supplementation results in a dramatic decrease in body fat mass in mice, but also causes considerable liver steatosis. However, little is known of the molecular mechanisms leading to hepatomegaly.