Podocyte and endothelial-specific elimination of BAMBI identifies differential transforming growth factor-β pathways contributing to diabetic glomerulopathy.

Transforming growth factor-β (TGF-β) is a central mediator of diabetic nephropathy. The effect of TGF-β, mediated by the type I TGF-β receptor, ALK5, and subsequent Smad2/3 activation results in podocyte apoptosis and loss. Previously, we demonstrated that the genetic deletion of the BMP and Activin Membrane-Bound Inhibitor (BAMBI), a negative modulator TGF-β signaling, accelerates diabetic nephropathy in mice.

Role of CD8+ T cells in crescentic glomerulonephritis.

Crescentic glomerulonephritis (cGN) comprises three main types according to the pathogenesis and immunofluorescence patterns: anti-glomerular basement membrane antibody cGN, vasculitis-associated cGN and post-infectious immune complex cGN. In this brief review of the immune-pathogenesis of cGN, the focus is mainly on the role of CD8+ T cells in the progression of cGN. Under control conditions, Bowman's capsule (BC) provides a protected immunological niche by preventing access of cytotoxic CD8+ T cells to Bowman's space and thereby podocytes.

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF--Induced Angiogenesis.

Background: Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich -2-glycoprotein 1 (LRG1).

Single-Cell RNA Profiling of Glomerular Cells Shows Dynamic Changes in Experimental Diabetic Kidney Disease.

Background: Recent single-cell RNA sequencing (scRNA-seq) analyses have offered much insight into cell-specific gene expression profiles in normal kidneys. However, in diseased kidneys, understanding of changes in specific cells, particularly glomerular cells, remains limited.

Methods: To elucidate the glomerular cell-specific gene expression changes in diabetic kidney disease, we performed scRNA-seq analysis of isolated glomerular cells from streptozotocin-induced diabetic endothelial nitric oxide synthase (eNOS)-deficient (eNOS) mice and control eNOS mice.

Bowman's capsule provides a protective niche for podocytes from cytotoxic CD8+ T cells.

T cells play a key role in immune-mediated glomerulonephritis, but how cytotoxic T cells interact with podocytes remains unclear. To address this, we injected EGFP-specific CD8+ T cells from just EGFP death inducing (Jedi) mice into transgenic mice with podocyte-specific expression of EGFP. In healthy mice, Jedi T cells could not access EGFP+ podocytes.

Gene expression profiles of glomerular endothelial cells support their role in the glomerulopathy of diabetic mice.

Endothelial dysfunction promotes the pathogenesis of diabetic nephropathy (DN), which is considered to be an early event in disease progression. However, the molecular changes associated with glomerular endothelial cell (GEC) injury in early DN are not well defined. Most gene expression studies have relied on the indirect assessment of GEC injury from isolated glomeruli or renal cortices.

Revisiting the determinants of the glomerular filtration barrier: what goes round must come round.

The glomerular filtration barrier (GFB) is characterized by a very high hydraulic permeability, combined with a marked permselectivity that excludes macromolecules such as albumin. Thus, the GFB retains most of the plasma proteins, with only 0.06% of albumin getting across the basement membrane.

Glomerular Endothelial Mitochondrial Dysfunction Is Essential and Characteristic of Diabetic Kidney Disease Susceptibility.

The molecular signaling mechanisms between glomerular cell types during initiation/progression of diabetic kidney disease (DKD) remain poorly understood. We compared the early transcriptome profile between DKD-resistant C57BL/6J and DKD-susceptible DBA/2J (D2) glomeruli and demonstrated a significant downregulation of essential mitochondrial genes in glomeruli from diabetic D2 mice, but not in C57BL/6J, with comparable hyperglycemia. Diabetic D2 mice manifested increased mitochondrial DNA lesions (8-oxoguanine) exclusively localized to glomerular endothelial cells after 3 weeks of diabetes, and these accumulated over time in addition to increased urine secretion of 8-oxo-deoxyguanosine.

Precision medicine comes of age in nephrology: identification of novel biomarkers and therapeutic targets for chronic kidney disease.

The goal of "precision medicine" is to characterize diseases based on the underlying molecular biology, in order to identify specific biomarkers and therapeutic targets that will ultimately improve clinical outcomes. The nephrology research community has developed a strong foundation for precision medicine, and recent publications demonstrate the feasibility of this approach to identify potential biomarkers and therapeutic targets in chronic kidney disease.

BAMBI elimination enhances alternative TGF-β signaling and glomerular dysfunction in diabetic mice.

BMP, activin, membrane-bound inhibitor (BAMBI) acts as a pseudo-receptor for the transforming growth factor (TGF)-β type I receptor family and a negative modulator of TGF-β kinase signaling, and BAMBI(-/-) mice show mild endothelial dysfunction. Because diabetic glomerular disease is associated with TGF-β overexpression and microvascular alterations, we examined the effect of diabetes on glomerular BAMBI mRNA levels. In isolated glomeruli from biopsies of patients with diabetic nephropathy and in glomeruli from mice with type 2 diabetes, BAMBI was downregulated.

Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro.

Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA (mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis.

Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.

Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease.

Are serum suPAR determinations by current ELISA methodology reliable diagnostic biomarkers for FSGS?

A soluble proteinuric substance has been postulated as a cause of primary focal segmental glomerulosclerosis (FSGS), and one candidate soluble urokinase receptor (suPAR). Evaluation of published results shows that serum suPAR determinations by current methodology do not reliably distinguish FSGS from other proteinuric glomerular diseases and serum suPAR cannot currently be considered a valid biomarker for primary or secondary FSGS. However, this should not discourage further research on potential roles of suPAR in proteinuric renal disease, including FSGS.

Epithelial cell TGFβ signaling induces acute tubular injury and interstitial inflammation.

TGFβ signaling plays a central role in the development of acute and chronic kidney diseases. Previous in vivo studies involved systemic alteration of TGFβ signaling, however, limiting conclusions about the direct role of TGFβ in tubular cell injury. Here, we generated a double transgenic mouse that inducibly expresses a ligand-independent constitutively active TGFβ receptor type 1 (TβR1) kinase specifically in tubular epithelial cells, with expression restricted by the Pax8 promoter.

Accelerated reendothelialization, increased neovascularization and erythrocyte extravasation after arterial injury in BAMBI-/- mice.

Background: Intimal injury rapidly activates TGFβ and enhances vascular repair by the growth of endothelial (EC) and vascular smooth muscle cells (VSMC). The response to the TGFβ family of growth factors can be modified by BAMBI (BMP, Activin, Membrane Bound Inhibitor) acting as a non-signaling, competitive antagonist of TGFβ type I receptors such as ALK 1 and 5. In vivo the effect of BAMBI will depend on its cell-specific expression and of that of the ALK type receptors.

BAMBI regulates angiogenesis and endothelial homeostasis through modulation of alternative TGFβ signaling.

Background: BAMBI is a type I TGFβ receptor antagonist, whose in vivo function remains unclear, as BAMBI(-/-) mice lack an obvious phenotype.

Methodology/principal Findings: Identifying BAMBI's functions requires identification of cell-specific expression of BAMBI. By immunohistology we found BAMBI expression restricted to endothelial cells and by electron microscopy BAMBI(-/-) mice showed prominent and swollen endothelial cells in myocardial and glomerular capillaries.

Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury.

Renal fibrosis and inflammation are associated with hypoxia, and tissue pO(2) plays a central role in modulating the progression of chronic kidney disease. Key mediators of cellular adaptation to hypoxia are hypoxia-inducible factor (HIF)-1 and -2. In the kidney, they are expressed in a cell type-specific manner; to what degree activation of each homolog modulates renal fibrogenesis and inflammation has not been established.

Activation of innate immune defense mechanisms contributes to polyomavirus BK-associated nephropathy.

Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic:polyribocytidylic acid (poly(I:C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct.

BAMBI is expressed in endothelial cells and is regulated by lysosomal/autolysosomal degradation.

Background: BAMBI (BMP and Activin Membrane Bound Inhibitor) is considered to influence TGFβ and Wnt signaling, and thereby fibrosis. Surprisingly data on cell type-specific expression of BAMBI are not available. We therefore examined the localization, gene regulation, and protein turnover of BAMBI in kidneys.