Role of the retinoic acid receptor-α in HIV-associated nephropathy.

All-trans retinoic acid protects against the development of HIV-associated nephropathy (HIVAN) in HIV-1 transgenic mice (Tg26). In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers by activating its receptor-α (RARα). Here, we report that Am580, a water-soluble RARα-specific agonist, attenuated proteinuria, glomerosclerosis, and podocyte proliferation, and restored podocyte differentiation markers in kidneys of Tg26 mice.

Protein kinase target discovery from genome-wide messenger RNA expression profiling.

Genome-wide messenger RNA profiling provides a snapshot of the global state of the cell under different experimental conditions such as diseased versus normal cellular states. However, because measurements are in the form of quantitative changes in messenger RNA levels, such experimental data does not provide direct understanding of the regulatory molecular mechanisms responsible for the observed changes. Identifying potential cell signaling regulatory mechanisms responsible for changes in gene expression under different experimental conditions or in different tissues has been the focus of many computational systems biology studies.

JAK/STAT signaling in renal diseases.

The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is a pleiotropic cascade essential to cytokine and growth hormone receptor signaling. Signaling through the JAK/STAT pathway is important for the kidney's response to injury in disease. Pang et al.

Up-regulation of the homophilic adhesion molecule sidekick-1 in podocytes contributes to glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease worldwide. Although the mechanisms underlying this important disease are poorly understood, the glomerular podocyte clearly plays a central role in disease pathogenesis. In the current work, we demonstrate that the homophilic adhesion molecule sidekick-1 (sdk-1) is up-regulated in podocytes in FSGS both in rodent models and in human kidney biopsy samples.

HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells.

Objective: HIV-associated nephropathy (HIVAN) is the most common cause of end-stage renal disease in persons with HIV/AIDS and is characterized by focal glomerulosclerosis and dysregulated renal tubular epithelial cell (RTEC) proliferation and apoptosis. HIV-1 viral protein r (Vpr) has been implicated in HIV-induced RTEC apoptosis but the mechanisms of Vpr-induced RTEC apoptosis are unknown. The aim of this study was therefore to determine the mechanisms of Vpr-induced apoptosis in RTEC.

Design of versatile biochemical switches that respond to amplitude, duration, and spatial cues.

Cells often mount ultrasensitive (switch-like) responses to stimuli. The design principles underlying many switches are not known. We computationally studied the switching behavior of GTPases, and found that this first-order kinetic system can show ultrasensitivity.

AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-delta: implications for vascular disease.

Advanced glycated end-product receptor 1 (AGER1) protects against vascular disease promoted by oxidants, such as advanced glycated end products (AGEs), via inhibition of reactive oxygen species (ROS). However, the specific AGEs, sources, and pathways involved remain undefined. The mechanism of cellular NADPH oxidase (NOX)-dependent ROS generation by defined AGEs, N(epsilon)-carboxymethyl-lysine- and methylglyoxal (MG)-modified BSA, was assessed in AGER1 overexpressing (AGER1(+) EC) or knockdown (sh-mRNA-AGER1(+) EC) human aortic endothelial (EC) and ECV304 cells, and aortic segments from old (18 mo) C57BL6-F(2) mice, propagated on low-AGE diet (LAGE), or LAGE supplemented with MG (LAGE+MG).

Reduction of Stat3 activity attenuates HIV-induced kidney injury.

HIV-1 Nef induces podocyte proliferation and dedifferentiation by activating the Stat3 and MAPK1,2 pathways. Activation of Stat3 also occurs in human kidneys affected by HIV-associated nephropathy (HIVAN), but its contribution to the development of HIVAN is unknown. Here, we generated HIV-1 transgenic mice (Tg26) with either 75% Stat3 activity (Tg26-SA/+) or 25% Stat3 activity (Tg26-SA/-).

AP-1 activated by toll-like receptors regulates expression of IL-23 p19.

Interleukin (IL)-23, a new member of the IL-12 family, plays a central role in the Th17 immune response and in autoimmune diseases. It is clear that activated macrophages and dendritic cells produce IL-23, but the molecular mechanisms whereby inflammatory signals stimulate IL-23 expression are not fully understood. We demonstrate that induction of IL-23 p19 gene expression by LPS depends on the TLR4 and MyD88 pathways.

Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy.

Recent studies suggest that Stat3, a transcription factor that mediates cytokine signaling, plays a critical role in the pathogenesis of diabetic nephropathy. Complete Stat3 gene knockout is embryonic lethal; therefore, we crossed Stat3+/- mice with Stat3 mutant mice (SA/SA) that lack full Stat3 activity. This strategy generated Stat3SA/- mice (25% activity) and Stat3SA/+ mice (75% activity), which were made diabetic using streptozotocin in order to define the role of Stat3 in diabetic kidney disease.

Signaling in regulation of podocyte phenotypes.

The kidney podocyte is a terminally differentiated and highly specialized cell. The function of the glomerular filtration barrier depends on the integrity of the podocyte. Podocyte injury and loss have been observed in human and experimental models of glomerular diseases.

ACTN4 gene mutations and single nucleotide polymorphisms in idiopathic focal segmental glomerulosclerosis.

Aim: To investigate the association between mutations or single nucleotide polymorphisms (SNPs) of the gene ACTN4 in Chinese patients with idiopathic focal segmental glomerulosclerosis (FSGS).

Materials And Methods: Genomic DNA of 82 Chinese idiopathic FSGS patients and 70 healthy people were used to analyze ACTN4 gene mutations by polymerase chain reaction, direct sequencing and GenBank matching. Hair follicle DNA of novel mutated patients' parents were sequenced and alpha-actinin-4 expression in patients' kidney was examined by immunofluorescence.

Retinoic acid utilizes CREB and USF1 in a transcriptional feed-forward loop in order to stimulate MKP1 expression in human immunodeficiency virus-infected podocytes.

Nef-induced podocyte proliferation and dedifferentiation via mitogen-activated protein kinase 1,2 (MAPK1,2) activation plays a role in human immunodeficiency virus (HIV) nephropathy pathogenesis. All-trans retinoic acid (atRA) reverses the HIV-induced podocyte phenotype by activating cyclic AMP (cAMP)/protein kinase A (PKA) and inhibiting MAPK1,2. Here we show that atRA, through cAMP and PKA, triggers a feed-forward loop involving CREB and USF1 to induce biphasic stimulation of MKP1.

Oral glycotoxins determine the effects of calorie restriction on oxidant stress, age-related diseases, and lifespan.

We previously showed that the content of advanced glycation end products (AGEs) in the diet correlates with serum AGE levels, oxidant stress (OS), organ dysfunction, and lifespan. We now show that the addition of a chemically defined AGE (methyl-glyoxal-BSA) to low-AGE mouse chow increased serum levels of AGEs and OS, demonstrating that dietary AGEs are oxidants that can induce systemic OS. OS predisposes to the development of cardiovascular and chronic kidney diseases; calorie restriction (CR) is the most studied means to decrease OS, increase longevity, and reduce OS-related organ damage in mammals.

Regulation of neurite outgrowth by G(i/o) signaling pathways.

Neurogenesis is a long and winding journey. A neural progenitor cell migrates long distances, differentiates by forming a single axon and multiple dendrites, undergoes maturation, and ultimately survives. The initial formation of neurites during neuronal differentiation, commonly referred to as "neurite outgrowth," can be induced by a large repertoire of signals that stimulate an array of receptors and downstream signaling pathways.

HIV-1 upregulates VEGF in podocytes.

HIV-associated nephropathy (HIVAN) is characterized by collapsing FSGS. Because transgenic mice with podocyte-specific overexpression of the vascular endothelial growth factor 164 (VEGF164) isoform also develop collapsing FSGS, we sought to determine whether VEGF plays a role in HIVAN. Compared with controls, immunohistochemistry revealed that kidneys from HIV-1-transgenic mice (Tg26) and from patients with HIVAN had greater expression of both VEGF and its transcriptional regulator, hypoxia-inducible factor 2alpha (HIF-2alpha).

Endothelial dysfunction in patients with chronic kidney disease results from advanced glycation end products (AGE)-mediated inhibition of endothelial nitric oxide synthase through RAGE activation.

Background And Objectives: Advanced glycation end products, known pro-inflammatory and pro-oxidative compounds that accumulate in patients with chronic kidney disease, may play a major role in their high prevalence of endothelial dysfunction and subsequent cardiovascular disease. This study examined the association of advanced glycation end product accumulation with cellular receptor for advanced glycation end product expression and endothelial dysfunction as well as the mechanisms of this association in chronic kidney disease.

Design, Setting, Participants, & Measurements: A cross-sectional study was conducted of ambulatory patients without diabetes and with different stages of chronic kidney disease (n = 51), compared with gender- and age-matched healthy subjects.

HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein.

The ability of the human immunodeficiency virus, type 1 (HIV-1) protein Nef to induce cytoskeleton changes in infected host cells is a key event in viral replication. In renal podocytes, we found that Nef induced loss of stress fibers and increased lamellipodia, pathological changes leading to proteinuria in HIV-associated nephropathy. These morphological changes were mediated by Nef-induced Rac1 activation and RhoA inhibition.

AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation.

Advanced glycation end products (AGEs) promote reactive oxygen species (ROS) formation and oxidant stress (OS) in diabetes and aging-related diseases. AGE-induced OS is suppressed by AGER1, an AGE-receptor that counteracts receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR)-mediated Shc/Ras signal activation, resulting in decreased OS. Akt, FKHRL1, and antioxidants; e.

Podocytes in HIV-associated nephropathy.

HIV-associated nephropathy (HIVAN) is the leading cause of end-stage renal failure in HIV-1 seropositive patients. The pathologic findings include collapsing focal segmental glomerulosclerosis with proliferation of epithelial cells in Bowman's space. Anatomically, these cells correspond to podocytes and exhibit a unique phenotype with loss of many differentiation markers including synaptopodin and dysregulation of the cell cycle markers consistent with proliferation.

Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression.

Aging is accompanied by increased oxidative stress (OS) and accumulation of advanced glycation end products (AGEs). AGE formation in food is temperature-regulated, and ingestion of nutrients prepared with excess heat promotes AGE formation, OS, and cardiovascular disease in mice. We hypothesized that sustained exposure to the high levels of pro-oxidant AGEs in normal diets (Reg(AGE)) contributes to aging via an increased AGE load, which causes AGER1 dysregulation and depletion of anti-oxidant capacity, and that an isocaloric, but AGE-restricted (by 50%) diet (Low(AGE)), would decrease these abnormalities.

Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway.

HIV-associated nephropathy is characterized by renal podocyte proliferation and dedifferentiation. This study found that all-trans retinoic acid (atRA) reverses the effects of HIV-1 infection in podocytes. Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1-infected podocytes.

Role of the Go/i signaling network in the regulation of neurite outgrowth.

Neurite outgrowth is a complex differentiation process stimulated by many neuronal growth factors and transmitters and by electrical activity. Among these stimuli are ligands for G-protein-coupled receptors (GPCR) that function as neurotransmitters. The pathways involved in GPCR-triggered neurite outgrowth are not fully understood.

Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor.

Advanced glycation end product receptors (AGERs) play distinct functional roles in both the toxicity and disposal of advanced glycation end products (AGEs), substances that are linked to diabetes and aging. Overexpression of AGER1 in murine mesangial cells (MCs) (MC-R1) inhibited AGE-induced MAPK1,2 phosphorylation and NF-kappaB activity and also increased AGE degradation. The mechanism of the inhibitory effects of AGER1, upstream of MAPK, was explored in MCs and HEK293 AGER1-expressing cells.

Animal models of HIV-associated nephropathy.

Purpose Of Review: HIV-1-associated nephropathy is characterized clinically by proteinuria with azotemia and pathologically by collapsing focal segmental glomerulosclerosis with tubulointerstitial nephritis and microcystic tubular dilatation. This review summarizes the manner in which different transgenic animal models contribute to our knowledge of the pathogenesis of HIV-1-associated nephropathy.

Recent Findings: The most widely studied has been a transgenic mouse model bearing a gag and pol-deleted proviral construct that develops renal disease with many of the clinical and pathologic characteristics seen in HIV-1-associated nephropathy.