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Hypertension (Dallas, Tex. : 1979) May 2022Macrophages play important roles in renal fibrosis, partially by sensing mechanical forces, including shear stress and increased stiffness. The mechanically activated...
BACKGROUND
Macrophages play important roles in renal fibrosis, partially by sensing mechanical forces, including shear stress and increased stiffness. The mechanically activated cationic channel Piezo1 drives vascular formation and blood pressure regulation to inflammatory responses, or cancer, but its role in macrophages in fibrotic kidney is elusive. Here, we hypothesized that Piezo1 in macrophages may have functions in renal fibrosis.
METHODS
We established a genetically engineered mouse model with specific knockout in myeloid cells and challenged with unilateral ureteric obstruction operation and folic acid treatment to induce the renal fibrosis, aiming to investigate the function of the mechanical-sensitive protein Piezo1 in macrophages in renal fibrosis and its underlying mechanisms.
RESULTS
Myeloid was indispensable for renal fibrosis generation. gene deletion in the myeloid lineage was protective in mice with renal fibrosis. Further analyses revealed that macrophage accumulation in the injured kidney depended on the Piezo1-regulated C-C motif chemokine ligand 2, C-C motif chemokine receptor 2 pathway, and Notch signaling cascade. Moreover, deletion restrained macrophage inflammation and consequently suppressed kidney fibrosis and epithelial-mesenchymal transition. In vitro assays showed that deficiency blocked lipopolysaccharide and Piezo1 activation-induced inflammatory responses in bone marrow-derived macrophages. Mechanistically, Piezo1 regulated inflammation through the Ca-dependent intracellular cysteine protease, as the pharmacological inhibition of calpain blocked the proinflammatory role of Piezo1.
CONCLUSIONS
This study characterized the important function of Piezo1 in renal fibrosis. Targeting the Piezo1 channels by genetic or pharmacological manipulations may be a promising strategy for the treatment of renal fibrosis.
Topics: Animals; Fibrosis; Inflammation; Ion Channels; Kidney; Kidney Diseases; Macrophages; Mice; Mice, Inbred C57BL
PubMed: 35417225
DOI: 10.1161/HYPERTENSIONAHA.121.18750 -
Journal of the American Society of... Dec 2020Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only...
BACKGROUND
Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease.
METHODS
Integrated droplet- and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney.
RESULTS
A single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses , before transitioning to become macrophages that accumulate in late injury. Conversely, a novel macrophage subset acts during repair.
CONCLUSIONS
Complementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.
Topics: Animals; Disease Models, Animal; Disease Progression; Kidney Diseases; Macrophages; Male; Mice; Mice, Inbred C57BL; Myeloid Cells; Sequence Analysis, RNA; Single-Cell Analysis; Ureteral Obstruction
PubMed: 32978267
DOI: 10.1681/ASN.2020060806 -
Annual Review of Physiology Feb 2020Autophagy is a cellular homeostatic program for the turnover of cellular organelles and proteins, in which double-membraned vesicles (autophagosomes) sequester... (Review)
Review
Autophagy is a cellular homeostatic program for the turnover of cellular organelles and proteins, in which double-membraned vesicles (autophagosomes) sequester cytoplasmic cargos, which are subsequently delivered to the lysosome for degradation. Emerging evidence implicates autophagy as an important modulator of human disease. Macroautophagy and selective autophagy (e.g., mitophagy, aggrephagy) can influence cellular processes, including cell death, inflammation, and immune responses, and thereby exert both adaptive and maladaptive roles in disease pathogenesis. Autophagy has been implicated in acute kidney injury, which can arise in response to nephrotoxins, sepsis, and ischemia/reperfusion, and in chronic kidney diseases. The latter includes comorbidities of diabetes and recent evidence for chronic obstructive pulmonary disease-associated kidney injury. Roles of autophagy in polycystic kidney disease and kidney cancer have also been described. Targeting the autophagy pathway may have therapeutic benefit in the treatment of kidney disorders.
Topics: Animals; Autophagy; Humans; Kidney Diseases; Mitophagy; Renal Insufficiency, Chronic
PubMed: 31640469
DOI: 10.1146/annurev-physiol-021119-034658 -
Advances in Chronic Kidney Disease Mar 2022The incidence of hematologic malignancies is on the rise worldwide. Kidney disease is ubiquitous in patients with hematologic malignancies, encompassing a wide spectrum... (Review)
Review
The incidence of hematologic malignancies is on the rise worldwide. Kidney disease is ubiquitous in patients with hematologic malignancies, encompassing a wide spectrum of disorders involving each kidney compartment, including the vasculature, tubules, interstitium, and glomerulus, and there is significant overlap of kidney involvement with each hematologic malignancy. Vascular disorders include both microvascular and macrovascular damage, via thrombotic microangiopathy, hyperleukocytosis, hyperviscosity, and cryoglobulinemia. The tubulointerstitial compartment may be affected by prerenal azotemia and acute tubular injury, but malignant infiltration, tumor lysis syndrome, extramedullary hematopoiesis, cast nephropathy, granulomatous interstitial nephritis, and lysozymuria should be considered in certain populations. Obstructive uropathy may occur due to nephrolithiasis or retroperitoneal fibrosis. Glomerular disorders, including membranoproliferative, membranous, minimal change, and focal segmental glomerulosclerosis, can rarely occur. By understanding how each compartment may be affected, care can best be optimized for these patients. In this review, we summarize the widely varied etiologies of kidney diseases stratified by kidney compartment and hematologic malignancy, focusing on demographics, pathology, pathophysiology, mechanism, and outcomes. We conclude with common electrolyte abnormalities associated with hematologic malignancies.
Topics: Glomerulosclerosis, Focal Segmental; Hematologic Neoplasms; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Nephritis, Interstitial
PubMed: 35817520
DOI: 10.1053/j.ackd.2022.02.003 -
Kidney International Jun 2020Extracellular vesicles such as exosomes are involved in mediating cell-cell communication by shuttling an assortment of proteins and genetic information. Here, we tested...
Extracellular vesicles such as exosomes are involved in mediating cell-cell communication by shuttling an assortment of proteins and genetic information. Here, we tested whether renal tubule-derived exosomes play a central role in mediating kidney fibrosis. The production of exosomes was found to be increased in the early stage of unilateral ureteral obstruction, ischemia reperfusion injury or 5/6 nephrectomy models of kidney disease. Exosome production occurred primarily in renal proximal tubular epithelium and was accompanied by induction of sonic hedgehog (Shh). In vitro, upon stimulation with transforming growth factor-β1, kidney proximal tubular cells (HKC-8) increased exosome production. Purified exosomes from these cells were able to induce renal interstitial fibroblast (NRK-49F) activation. Conversely, pharmacologic inhibition of exosome secretion with dimethyl amiloride, depletion of exosome from the conditioned media or knockdown of Shh expression abolished the ability of transforming growth factor-β1-treated HKC-8 cells to induce NRK-49F activation. In vivo, injections of tubular cell-derived exosomes aggravated kidney injury and fibrosis, which was negated by an Shh signaling inhibitor. Blockade of exosome secretion in vivo ameliorated renal fibrosis after either ischemic or obstructive injury. Furthermore, knockdown of Rab27a, a protein that is essential for exosome formation, also preserved kidney function and attenuated renal fibrotic lesions in mice. Thus, our results suggest that tubule-derived exosomes play an essential role in renal fibrogenesis through shuttling Shh ligand. Hence, strategies targeting exosomes could be a new avenue in developing therapeutics against renal fibrosis.
Topics: Animals; Exosomes; Fibroblasts; Fibrosis; Hedgehog Proteins; Kidney; Kidney Diseases; Mice; Transforming Growth Factor beta1
PubMed: 32139089
DOI: 10.1016/j.kint.2019.11.026 -
Clinical Science (London, England :... Feb 2022Renovascular disease (RVD) remains a common etiology of secondary hypertension. Recent clinical trials revealed unsatisfactory therapeutic outcomes of renal... (Review)
Review
Renovascular disease (RVD) remains a common etiology of secondary hypertension. Recent clinical trials revealed unsatisfactory therapeutic outcomes of renal revascularization, leading to extensive investigation to unravel key pathophysiological mechanisms underlying irreversible functional loss and structural damage in the chronically ischemic kidney. Research studies identified complex interactions among various players, including inflammation, fibrosis, mitochondrial injury, cellular senescence, and microvascular remodeling. This interplay resulted in a shift of our understanding of RVD from a mere hemodynamic disorder to a pro-inflammatory and pro-fibrotic pathology strongly influenced by systemic diseases like metabolic syndrome (MetS), hypertension, diabetes mellitus, and hyperlipidemia. Novel diagnostic approaches have been tested for early detection and follow-up of RVD progression, using new imaging techniques and biochemical markers of renal injury and dysfunction. Therapies targeting some of the pathological pathways governing the development of RVD have shown promising results in animal models, and a few have moved from bench to clinical research. This review summarizes evolving understanding in chronic ischemic kidney injury.
Topics: Animals; Fibrosis; Humans; Hypertension, Renovascular; Inflammation; Ischemia; Kidney; Kidney Diseases; Renal Artery Obstruction; Renal Circulation
PubMed: 35129198
DOI: 10.1042/CS20210509 -
Cellular Signalling Feb 2022Phosphodiesterase subtype 4 (PDE4) hydrolyzes cyclic AMP, a secondary messenger that mediates intracellular signaling, and plays key roles in inflammatory and fibrotic... (Review)
Review
Phosphodiesterase subtype 4 (PDE4) hydrolyzes cyclic AMP, a secondary messenger that mediates intracellular signaling, and plays key roles in inflammatory and fibrotic responses. Based on these significant anti-inflammatory effects, oral administration of PDE4 inhibitor is approved for the treatment of chronic obstructive pulmonary disease, atopic dermatitis, and psoriasis. However, PDE4 inhibition also has adverse effects, such as diarrhea, vomiting, dyspepsia, and headache. Therefore, the application of PDE4 inhibitors for chronic diseases, such as diabetes and its complications, has not yet been approved. Recent studies have reported the clinical benefits of pentoxifylline, a non-selective PDE inhibitor, in patients with kidney disease. The PDE4 inhibitor, roflumilast, also clearly ameliorates the symptoms of diabetes mellitus by improving hyperglycemia and insulin resistance. However, the beneficial effects of PDE4 inhibition on diabetic nephropathy have not yet been evaluated, and its potential mechanisms of action remain unknown. In this review, we discuss the beneficial effects of PDE4 inhibitors and their mechanisms of action using diabetes and DN models.
Topics: Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Diabetes Mellitus; Diabetic Nephropathies; Humans; Phosphodiesterase 4 Inhibitors
PubMed: 34785349
DOI: 10.1016/j.cellsig.2021.110185 -
Presse Medicale (Paris, France : 1983) Apr 2020IgG4-RD may affect several organs including kidneys. The kidney is involved in approximately 20% of patient with IgG4-RD. The most common intrinsic kidney disease is... (Review)
Review
IgG4-RD may affect several organs including kidneys. The kidney is involved in approximately 20% of patient with IgG4-RD. The most common intrinsic kidney disease is tubulointerstitial nephritis (IgG4-TIN). Retroperitoneal fibrosis (IgG4-RPF) may induce obstructive acute renal failure. More rarely, IgG4-RKD can manifest as a glomerular disease, in particular as a membranous nephropathy (MN). It mostly affects middle-aged to elderly men and causes acute or chronic renal dysfunction, multiple hypodense lesions on CT-Scan and various extra-renal lesions. Increased serum IgG4 and hypocomplementemia are the most important serological findings for the diagnosis of IgG4-RD and thus should be systematically assessed when IgG4-RKD is suspected. Specific diagnosis criteria for IgG4-TIN including interstitial infiltration of IgG4-positive plasma cells, storiform fibrosis and tubular basement membrane immune complex deposits have been proposed. Corticosteroids are effective and remain the first-line therapy but relapses or severe forms could respond to immunosuppressive therapy.
Topics: Acute Kidney Injury; Creatinine; Female; Glomerulonephritis, Membranous; Humans; Immunoglobulin G; Immunoglobulin G4-Related Disease; Kidney; Kidney Diseases; Male; Middle Aged; Nephritis, Interstitial; Retroperitoneal Fibrosis; Steroids
PubMed: 32234380
DOI: 10.1016/j.lpm.2020.104017 -
Advances in Experimental Medicine and... 2023Hypertension implicates multiple organs and systems, accounting for the majority of cardiovascular diseases and cardiac death worldwide. Extracellular vesicles derived...
Hypertension implicates multiple organs and systems, accounting for the majority of cardiovascular diseases and cardiac death worldwide. Extracellular vesicles derived from various types of cells could transfer a variety of substances such as proteins, lipids, and nucleic acids from cells to cells, playing essential roles in both physiological and pathological processes. Extracellular vesicles are demonstrated to be closely associated with the development of essential hypertension by mediating the renin-angiotensin-aldosterone system and crosstalk between multiple vascular cells. Extracellular vesicles also participate in various kinds of pathogenesis of secondary hypertensions including acute kidney injury, renal parenchymal diseases, kidney transplantation, secretory diseases (primary aldosteronism, pheochromocytoma and paraganglioma, Cushing's syndrome), and obstructive sleep apnea. Extracellular vesicles have been proved to have the potential to be served as new biomarkers in the diagnosis, treatment, and prognosis assessment of hypertension. In the future, large multicenter cohorts are highly in demand for further verifying the sensitivity and specificity of extracellular vesicles as biomarkers.
Topics: Hypertension; Extracellular Vesicles; Humans; Kidney Diseases
PubMed: 37603273
DOI: 10.1007/978-981-99-1443-2_5 -
Pediatric Nephrology (Berlin, Germany) Apr 2022Over the years, hyaluronic acid (HA) has emerged as an important molecule in nephrological and urological studies involving extracellular matrix (ECM) organization,... (Review)
Review
Over the years, hyaluronic acid (HA) has emerged as an important molecule in nephrological and urological studies involving extracellular matrix (ECM) organization, inflammation, tissue regeneration, and viral sensing. During this time, many have noted the perplexing double-edged nature of the molecule, at times promoting pro-fibrotic events and at other times promoting anti-fibrotic events. Different molecular weights of HA can be attributed to these disparities, though most studies have yet to focus on this subtlety. With regard to the kidney, HA is induced in the initial response phase of injury and is subsequently decreased during disease progression of AKI, CKD, and diabetic nephropathy. These and other kidney diseases force patients, particularly pediatric patients, to face dialysis, surgical procedures, and ultimately, transplant. To summarize the current literature for researchers and pediatric nephrologists, this review aims to expound HA and elucidate its paradoxical effects in multiple kidney diseases using studies that emphasize HA molecular weight when available.
Topics: Child; Diabetic Nephropathies; Fibrosis; Humans; Hyaluronic Acid; Kidney; Renal Dialysis
PubMed: 34009465
DOI: 10.1007/s00467-021-05113-9