In the past decade, our understanding of the role of podocytes in the function of the glomerular filtration barrier, and of the role of podocyte injury in the pathogenesis of proteinuric kidney ...disease, has substantially increased. Landmark genetic studies identified mutations in genes expressed by podocytes as a cause of albuminuria and nephrotic syndrome, leading to breakthrough discoveries from many laboratories. These discoveries contributed to a dramatic change in our view of the glomerular filtration barrier of the kidney and of the role of podocyte injury in the development of albuminuria and progressive kidney disease. In the past several years, studies have demonstrated that podocyte injury is a major cause of marked albuminuria and nephrotic syndrome, and have confirmed that podocytes are important for the maintenance of an intact glomerular filtration barrier. An essential role of loss of these cells in the pathogenesis of glomerulosclerosis and progressive proteinuric kidney disease has also been identified. In this Review, we discuss the importance of podocytes for the maintenance of an intact glomerular filtration barrier and their role in albumin handling.
APOE is the strongest genetic risk factor for late-onset Alzheimer’s disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates ...microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here, we show that overexpressing an apoE metabolic receptor, LDLR (low-density lipoprotein receptor), in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression and is associated with suppressed microglial activation as in apoE-deficient microglia. ApoE deficiency and LDLR OX strongly drive microglial immunometabolism toward enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs) and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy.
•LDLR OX lowers apoE and reduces tau pathology and neurodegeneration in P301S mice•LDLR-overexpressing microglia downregulate Apoe and show suppressed activation•ApoE KO and LDLR OX drive microglial catabolism over anabolism•ApoE KO and LDLR OX increase the OPC pool and preserve myelin integrity
Shi et al. show that apoE regulates tau-associated neurodegeneration via multiple mechanisms, including regulating microglial activation by controlling microglial immunometabolism, regulating OPCs and myelin integrity, and regulating reactive astrocyte activation. LDLR overexpression attenuates tauopathy in part through shared mechanisms of apoE, making LDLR a new therapeutic target for tauopathy treatment.
Chronic neuroinflammation is a pathogenic component of Alzheimer’s disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune ...system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune‐cell checkpoint receptor/ligand pair PD‐1/PD‐L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD‐L1 and PD‐1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD‐L1 from astrocytes, which may mediate ectodomain signaling to PD‐1‐expressing microglia. Deletion of microglial PD‐1 evoked an inflammatory response and compromised amyloid‐β peptide (Aβ) uptake. APP/PS1 mice deficient for PD‐1 exhibited increased deposition of Aβ, reduced microglial Aβ uptake, and decreased expression of the Aβ receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD‐1/PD‐L1 axis contributes to Aβ plaque deposition during chronic neuroinflammation in AD.
SYNOPSIS
Neuroinflammation, a hallmark of Alzheimer’s disease (AD), is involved in beta‐amyloid peptide (Aβ) plaque deposition and clearance. Here, the PD‐1/PD‐L1 axis is found as an important pathway for regulating the immune system in the brain, sustaining microglial Aβ uptake and reducing chronic neuroinflammation.
Astrocytic PD‐L1 and microglial PD‐1 are upregulated around Aβ plaques in Alzheimer’s disease (AD) and APP/PS1 mice.
PD‐L1 is secreted in a soluble form by astrocytes in culture.
PD‐1 deficiency compromises Aβ phagocytosis and induces an inflammatory response in vitro.
Loss of PD‐1 increases Aβ plaque deposition and reduces microglial Aβ uptake in APP/PS1 mice.
The immune‐checkpoint receptor/ligand pair PD‐1/PD‐L1 sustains phagocytic function of microglia to prevent Aβ plaque deposition in APP/PS mouse models and patient tissues.
The cellular responses induced by mitochondrial dysfunction remain elusive. Intrigued by the lack of almost any glomerular phenotype in patients with profound renal ischemia, we comprehensively ...investigated the primary sources of energy of glomerular podocytes. Combining functional measurements of oxygen consumption rates, glomerular metabolite analysis, and determination of mitochondrial density of podocytes in vivo, we demonstrate that anaerobic glycolysis and fermentation of glucose to lactate represent the key energy source of podocytes. Under physiological conditions, we could detect neither a developmental nor late-onset pathological phenotype in podocytes with impaired mitochondrial biogenesis machinery, defective mitochondrial fusion-fission apparatus, or reduced mtDNA stability and transcription caused by podocyte-specific deletion of Pgc-1α, Drp1, or Tfam, respectively. Anaerobic glycolysis represents the predominant metabolic pathway of podocytes. These findings offer a strategy to therapeutically interfere with the enhanced podocyte metabolism in various progressive kidney diseases, such as diabetic nephropathy or focal segmental glomerulosclerosis (FSGS).
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•Anaerobic glycolysis represents the predominant energy source of podocytes•Neither mitochondrial turnover nor mtDNA transcription impairs podocyte function•These findings elucidate podocyte metabolism, function, and glomerular integrity
Glomerular podocytes form the third and most outer layer of the kidney filtration barrier responsible for restricting the passage of proteins into the urine. Brinkkoetter et al. show that podocyte metabolism primarily relies on anaerobic glycolysis and the fermentation of glucose to lactate.
Inflammation conveys the development of glomerular injury and is a major cause of progressive kidney disease. NF-κB signaling is among the most important regulators of proinflammatory signaling. Its ...role in podocytes, the epithelial cells at the kidney filtration barrier, is poorly understood. Here, we inhibited NF-κB signaling in podocytes by specific ablation of the NF-κB essential modulator (NEMO, IKKγ). Podocyte-specific NEMO-deficient mice (NEMO(pko)) were viable and did not show proteinuria or overt changes in kidney morphology. After induction of glomerulonephritis, both NEMO(pko) and control mice developed significant proteinuria. However, NEMO(pko) mice recovered much faster, showing rapid remission of proteinuria and restoration of podocyte morphology. Interestingly, quantification of infiltrating macrophages, T-lymphocytes, and granulocytes at day 7 revealed no significant difference between wild-type and NEMO(pko). To further investigate the underlying mechanisms, we created a stable NEMO knockdown mouse podocyte cell line. Again, no overt changes in morphology were observed. Translocation of NF-κB to the nucleus after stimulation with TNFα or IL-1 was sufficiently inhibited. Moreover, secretion of proinflammatory chemokines from podocytes after stimulation with TNFα or IL-1 was significantly reduced in NEMO-deficient podocytes and in glomerular samples obtained at day 7 after induction of nephrotoxic nephritis. Collectively, these results show that proinflammatory activity of NF-κB in podocytes aggravates proteinuria in experimental glomerulonephritis in mice. Based on these data, it may be speculated that immunosuppressive drugs may not only target professional immune cells but also podocytes directly to convey their beneficial effects in various types of glomerulonephritis.
Podocytes, the visceral epithelial cells of the kidney glomerulus, elaborate primary and interdigitating secondary extensions to enwrap the glomerular capillaries. A hallmark of podocyte injury is ...the loss of unique ultrastructure and simplification of the cell shape, called foot process effacement, which is a classic feature of proteinuric kidney disease. Although several key pathways have been identified that control cytoskeletal regulation, actin dynamics, and polarity signaling, studies into the dynamic regulation of the podocyte structure have been hampered by the fact that ultrastructural analyses require electron microscopic imaging of fixed tissue. We developed a new technique that allows for visualization of podocyte foot processes using confocal laser scanning microscopy. The combination of inducible and mosaic expression of membrane-tagged fluorescent proteins in a small subset of podocytes enabled us to acquire light microscopic images of podocyte foot processes in unprecedented detail, even in living podocytes of freshly isolated glomeruli. Moreover, this technique visualized oscillatory glomerular contractions and confirmed the morphometric evaluations obtained in static electron microscopic images of podocyte processes. These data suggest that the new technique will provide an extremely powerful tool for studying the dynamics of podocyte ultrastructure.
Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Loss of the ...stomatin/PHB/flotillin/HflK/C (SPFH) domain containing protein PHB2 causes mitochondrial dysfunction and defective mitochondria-mediated signaling, which is implicated in a variety of human diseases, including progressive renal disease. Here, we provide evidence of additional, extra-mitochondrial functions of this membrane-anchored protein. Immunofluorescence and immunogold labeling detected PHB2 at mitochondrial membranes and at the slit diaphragm, a specialized cell junction at the filtration slit of glomerular podocytes. PHB2 coprecipitated with podocin, another SPFH domain-containing protein, essential for the assembly of the slit diaphragm protein-lipid supercomplex. Consistent with an evolutionarily conserved extra-mitochondrial function, the ortholog of PHB2 in Caenorhabditis elegans was also not restricted to mitochondria but colocalized with the mechanosensory complex that requires the podocin ortholog MEC2 for assembly. Knockdown of phb-2 partially phenocopied loss of mec-2 in touch neurons of the nematode, resulting in impaired gentle touch sensitivity. Collectively, these data indicate that, besides its established role in mitochondria, PHB2 may have an additional function in conserved protein–lipid complexes at the plasma membrane.
Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and ...requires the prohibitin ring complex subunit prohibitin‐2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF‐1 signaling. Deletion of PHB2 in podocytes of mice, terminally differentiated cells at the kidney filtration barrier, caused progressive proteinuria, kidney failure, and death of the animals and resulted in hyperphosphorylation of S6 ribosomal protein (S6RP), a known mediator of the mTOR signaling pathway. Inhibition of the insulin/IGF‐1 signaling system through genetic deletion of the insulin receptor alone or in combination with the IGF‐1 receptor or treatment with rapamycin prevented hyperphosphorylation of S6RP without affecting the mitochondrial structural defect, alleviated renal disease, and delayed the onset of kidney failure in PHB2‐deficient animals. Evidently, perturbation of insulin/IGF‐1 receptor signaling contributes to tissue damage in mitochondrial disease, which may allow therapeutic intervention against a wide spectrum of diseases.
Synopsis
Podocyte‐specific PHB2 loss results in severe kidney disease that is alleviated by insulin and IGF‐1 receptors deletion or rapamycin treatment, demonstrating not only a causal link between mitochondrial dysfunction and kidney disease but also putative therapeutic avenues.
Deletion of the mitochondrial protein PHB2 in glomerular podocytes caused progressive proteinuria and death of the animals due to end‐stage kidney failure.
Contrary to generally held beliefs loss of PHB2 did not cause overt defects in mitochondrial respiratory activity or increased production of ROS but was accompanied by hyperactive insulin/IGF‐1 receptor signaling.
Inhibition of the insulin/IGF‐1 signaling system through genetic deletion of insulin receptor alone or in combination with the IGF‐1 receptor or treatment with mTOR inhibitor rapamycin, alleviated renal disease and delayed the onset of kidney failure in PHB2‐deficient animals.
Podocyte‐specific PHB2 loss results in severe kidney disease that is alleviated by insulin and IGF‐1 receptors deletion or rapamycin treatment, demonstrating not only a causal link between mitochondrial dysfunction and kidney disease but also putative therapeutic avenues.
Over the past decades, our view on neurodegenerative diseases has been mainly centered around neurons and their networks. Only recently it became evident that immunological processes arise alongside ...degenerating neurons, raising the question whether these represent just meaningless bystander reactions or in turn, contribute to pathogenesis and disease symptoms. When considering any effect of inflammatory events on the CNS one has to consider the site, duration and nature of immune activation. Likewise, one has to distinguish between mechanisms which directly impact the neuronal compartment and indirect mechanisms, which affect cells that are important for neuronal functioning and survival. As discussed in this review, both types of mechanisms may be present at the same time and additively or synergistically lead to neuronal demise. Inflammatory mediators released by the principle innate immune cells of the brain, microglia and astrocytes, can compromise the function and structure of neurons, thereby playing important roles in the pathogenesis of neurodegenerative diseases.
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