Chronic kidney disease (CKD) is a global health problem. CKD patients are at high risk of developing cardiovascular disease (CVD), including coronary artery disease, heart failure and stroke. Several ...factors invoke a vicious cycle of CKD and CVD, which is referred as to “cardiorenal syndrome”. Among these factors, the compounds retained through loss of renal excretion play a pathological role in causing atherosclerosis and CVD. These compounds have been broadly classified as uremic toxins because of their accumulation with declining renal function and cytotoxicity. The major uremic toxins contributing to CVD are asymmetric dimethylarginine (ADMA), advanced glycation endproducts (AGE), and trimethyl amine N-oxide (TMAO). ADMA is linked to CVD through regulation of nitric oxide, reactive oxygen species, and renal anemia. AGE not only directly accumulates in the heart and kidney, but interacts with the receptor for AGE (RAGE), leading to cell damage in CVD. TMAO correlates with a high prevalence of CVD and promotes organ fibrosis by itself. The levels of these and other uremic toxins rise with worsening CKD, inducing multiplicative damage in the heart and kidney. Therefore, a better understanding of uremic toxins has great clinical importance for preventing cardiorenal syndrome. This review highlights the molecular mechanism by which these uremic toxins are implicated in CVD and suggests the possible mutual relationship between them.
Phagocytosis of apoptotic cells by both professional and semi‐professional phagocytes is required for resolution of organ damage and maintenance of immune tolerance. KIM‐1/TIM‐1 is a ...phosphatidylserine receptor that is expressed on epithelial cells and can transform the cells into phagocytes. Here, we demonstrate that KIM‐1 phosphorylation and association with p85 results in encapsulation of phagosomes by lipidated LC3 in multi‐membrane organelles. KIM‐1‐mediated phagocytosis is not associated with increased ROS production, and NOX inhibition does not block LC3 lipidation. Autophagy gene expression is required for efficient clearance of apoptotic cells and phagosome maturation. KIM‐1‐mediated phagocytosis leads to pro‐tolerogenic antigen presentation, which suppresses CD4 T‐cell proliferation and increases the percentage of regulatory T cells in an autophagy gene‐dependent manner. Taken together, these data reveal a novel mechanism of epithelial biology linking phagocytosis, autophagy and antigen presentation to regulation of the inflammatory response.
Synopsis
This study reveals how KIM‐1/TIM‐1‐mediated phagocytosis down‐modulates inflammation through ATG5 and ULK1‐dependent autophagic processing of phagocytosed material to MHC I and MHC II.
Phagocytosis of apoptotic cells by KIM‐1, a non‐myeloid phagocytosis receptor, induces LC3 lipidation of resulting phagosomes.
Autophagy protein expression, ATG5, ULK1 and Beclin1, are required for LC3 targeting to phagosomes and efficient phagosome acidification and maturation.
KIM‐1 signaling via the PI3 kinase subunit p85 promotes LC3 lipidation and accumulation on phagosomes.
Phagocytosed material processed through autophagy is presented to MHC I and MHC II.
Enhanced antigen presentation resulting from autophagic processing results in a pro‐tolerogenic milieu, reducing the percentage of CD4 effector T cells while increasing the percentage of regulatory T cells.
Phosphatidylserine receptor KIM‐1/TIM‐1‐mediated phagocytosis and autophagic processing of apoptotic cells promote antigen presentation in epithelial cells to modulate inflammation.
Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), ...resulting in aberrant incomplete repair, is a major contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH(2)-terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.
Kidney injury molecule 1 (KIM-1, also known as TIM-1) is markedly upregulated in the proximal tubule after injury and is maladaptive when chronically expressed. Here, we determined that early in the ...injury process, however, KIM-1 expression is antiinflammatory due to its mediation of phagocytic processes in tubule cells. Using various models of acute kidney injury (AKI) and mice expressing mutant forms of KIM-1, we demonstrated a mucin domain-dependent protective effect of epithelial KIM-1 expression that involves downregulation of innate immunity. Deletion of the mucin domain markedly impaired KIM-1-mediated phagocytic function, resulting in increased proinflammatory cytokine production, decreased antiinflammatory growth factor secretion by proximal epithelial cells, and a subsequent increase in tissue macrophages. Mice expressing KIM-1Δmucin had greater functional impairment, inflammatory responses, and mortality in response to ischemia- and cisplatin-induced AKI. Compared with primary renal proximal tubule cells isolated from KIM-1Δmucin mice, those from WT mice had reduced proinflammatory cytokine secretion and impaired macrophage activation. The antiinflammatory effect of KIM-1 expression was due to the interaction of KIM-1 with p85 and subsequent PI3K-dependent downmodulation of NF-κB. Hence, KIM-1-mediated epithelial cell phagocytosis of apoptotic cells protects the kidney after acute injury by downregulating innate immunity and inflammation.
T cell Ig and mucin domain (Tim)-1 identifies IL-10-producing regulatory B cells (Bregs). Mice on the C57BL/6 background harboring a loss-of-function Tim-1 mutant showed progressive loss of IL-10 ...production in B cells and with age developed severe multiorgan tissue inflammation. We demonstrate that Tim-1 expression and signaling in Bregs are required for optimal production of IL-10. B cells with Tim-1 defects have impaired IL-10 production but increased proinflammatory cytokine production, including IL-1 and IL-6. Tim-1-deficient B cells promote Th1 and Th17 responses but inhibit the generation of regulatory T cells (Foxp3(+) and IL-10-producing type 1 regulatory T cells) and enhance the severity of experimental autoimmune encephalomyelitis. Mechanistically, Tim-1 on Bregs is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production in Bregs. Treatment with ACs reduces the severity of experimental autoimmune encephalomyelitis in hosts with wild-type but not Tim-1-deficient Bregs. Collectively, these findings suggest that in addition to serving as a marker for identifying IL-10-producing Bregs, Tim-1 is also critical for maintaining self-tolerance by regulating IL-10 production in Bregs.
A critical event during kidney organogenesis is the differentiation of podocytes, specialized epithelial cells that filter blood plasma to form urine. Podocytes derived from human pluripotent stem ...cells (hPSC‐podocytes) have recently been generated in nephron‐like kidney organoids, but the developmental stage of these cells and their capacity to reveal disease mechanisms remains unclear. Here, we show that hPSC‐podocytes phenocopy mammalian podocytes at the capillary loop stage (CLS), recapitulating key features of ultrastructure, gene expression, and mutant phenotype. hPSC‐podocytes in vitro progressively establish junction‐rich basal membranes (nephrin+podocin+ZO‐1+) and microvillus‐rich apical membranes (podocalyxin+), similar to CLS podocytes in vivo. Ultrastructural, biophysical, and transcriptomic analysis of podocalyxin‐knockout hPSCs and derived podocytes, generated using CRISPR/Cas9, reveals defects in the assembly of microvilli and lateral spaces between developing podocytes, resulting in failed junctional migration. These defects are phenocopied in CLS glomeruli of podocalyxin‐deficient mice, which cannot produce urine, thereby demonstrating that podocalyxin has a conserved and essential role in mammalian podocyte maturation. Defining the maturity of hPSC‐podocytes and their capacity to reveal and recapitulate pathophysiological mechanisms establishes a powerful framework for studying human kidney disease and regeneration. Stem Cells 2017;35:2366–2378
Comparison of stem cell‐derived human kidney organoids in vitro with genetic mouse models in vivo reveals that podocytes (red), the filtering cells of the kidney, undergo apical‐to‐basal junctional migration at the capillary loop stage. A critical player in this process is podocalyxin, which induces negatively charged microvilli between neighboring podocytes, pushing them apart.
Human-pluripotent-stem-cell-derived kidney cells (hPSC-KCs) have important potential for disease modelling and regeneration. Whether the hPSC-KCs can reconstitute tissue-specific phenotypes is ...currently unknown. Here we show that hPSC-KCs self-organize into kidney organoids that functionally recapitulate tissue-specific epithelial physiology, including disease phenotypes after genome editing. In three-dimensional cultures, epiblast-stage hPSCs form spheroids surrounding hollow, amniotic-like cavities. GSK3β inhibition differentiates spheroids into segmented, nephron-like kidney organoids containing cell populations with characteristics of proximal tubules, podocytes and endothelium. Tubules accumulate dextran and methotrexate transport cargoes, and express kidney injury molecule-1 after nephrotoxic chemical injury. CRISPR/Cas9 knockout of podocalyxin causes junctional organization defects in podocyte-like cells. Knockout of the polycystic kidney disease genes PKD1 or PKD2 induces cyst formation from kidney tubules. All of these functional phenotypes are distinct from effects in epiblast spheroids, indicating that they are tissue specific. Our findings establish a reproducible, versatile three-dimensional framework for human epithelial disease modelling and regenerative medicine applications.
Fibrosis contributes to the progression of chronic kidney disease (CKD). Severe acute kidney injury can lead to CKD through proximal tubular cell (PTC) cycle arrest in the G
-M phase, with secretion ...of profibrotic factors. Here, we show that epithelial cells in the G
-M phase form target of rapamycin (TOR)-autophagy spatial coupling compartments (TASCCs), which promote profibrotic secretion similar to the senescence-associated secretory phenotype. Cyclin G1 (CG1), an atypical cyclin, promoted G
-M arrest in PTCs and up-regulated TASCC formation. PTC TASCC formation was also present in humans with CKD. Prevention of TASCC formation in cultured PTCs blocked secretion of profibrotic factors. PTC-specific knockout of a key TASCC component reduced the rate of kidney fibrosis progression in mice with CKD. CG1 induction and TASCC formation also occur in liver fibrosis. Deletion of CG1 reduced G
-M phase cells and TASCC formation in vivo. This study provides mechanistic evidence supporting how profibrotic G
-M arrest is induced in kidney injury and how G
-M-arrested PTCs promote fibrosis, identifying new therapeutic targets to mitigate kidney fibrosis.
Tubulointerstitial abnormalities are predictive of the progression of diabetic kidney disease (DKD), and their targeting may be an effective means for prevention. Proximal tubular (PT) expression of ...kidney injury molecule (KIM)-1, as well as blood and urinary levels, are increased early in human diabetes and can predict the rate of disease progression. Here, we report that KIM-1 mediates PT uptake of palmitic acid (PA)-bound albumin, leading to enhanced tubule injury with DNA damage, PT cell-cycle arrest, interstitial inflammation and fibrosis, and secondary glomerulosclerosis. Such injury can be ameliorated by genetic ablation of the KIM-1 mucin domain in a high-fat-fed streptozotocin mouse model of DKD. We also identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed in vivo in a kidney injury model in mice that it ameliorates renal inflammation and fibrosis. Together, our findings support KIM-1 as a new therapeutic target for DKD.
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•KIM-1 is expressed in proximal tubules of humans with diabetic kidney disease•KIM-1 mediates the endocytic uptake of palmitic acid (PA)-bound albumin•KIM-1-mediated PA-albumin uptake leads to interstitial inflammation and fibrosis•TW-37 prevents KIM-1-mediated PA-albumin uptake and ameliorates tubular injury
Mori et al. report that during diabetic kidney disease KIM-1 mediates proximal tubular uptake of palmitic acid-bound albumin, leading to enhanced tubule injury with interstitial inflammation and fibrosis, as well as secondary glomerulosclerosis. Further, they identify a small molecule inhibitor of KIM-1, TW-37, that can ameliorate the injury.
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