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Physiological Reviews Oct 2023The kidneys play a key role in maintaining total body homeostasis. The complexity of this task is reflected in the unique architecture of the organ. Ureteral obstruction... (Review)
Review
The kidneys play a key role in maintaining total body homeostasis. The complexity of this task is reflected in the unique architecture of the organ. Ureteral obstruction greatly affects renal physiology by altering hemodynamics, changing glomerular filtration and renal metabolism, and inducing architectural malformations of the kidney parenchyma, most importantly renal fibrosis. Persisting pathological changes lead to chronic kidney disease, which currently affects ∼10% of the global population and is one of the major causes of death worldwide. Studies on the consequences of ureteral obstruction date back to the 1800s. Even today, experimental unilateral ureteral obstruction (UUO) remains the standard model for tubulointerstitial fibrosis. However, the model has certain limitations when it comes to studying tubular injury and repair, as well as a limited potential for human translation. Nevertheless, ureteral obstruction has provided the scientific community with a wealth of knowledge on renal (patho)physiology. With the introduction of advanced omics techniques, the classical UUO model has remained relevant to this day and has been instrumental in understanding renal fibrosis at the molecular, genomic, and cellular levels. This review details key concepts and recent advances in the understanding of obstructive nephropathy, highlighting the pathophysiological hallmarks responsible for the functional and architectural changes induced by ureteral obstruction, with a special emphasis on renal fibrosis.
Topics: Humans; Animals; Ureteral Obstruction; Kidney; Renal Insufficiency, Chronic; Hemodynamics; Fibrosis; Disease Models, Animal
PubMed: 37440209
DOI: 10.1152/physrev.00027.2022 -
Cell Death and Differentiation Aug 2021Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated....
Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated. Here, we showed that Gasdermin E (GSDME) expression level and GSDME-N domain generation determined the RTC fate response to TNFα under the condition of oxygen-glucose-serum deprivation. Deletion of Caspase-3 (Casp3) or Gsdme alleviated renal tubule damage and inflammation and finally prevented the development of hydronephrosis and kidney fibrosis after ureteral obstruction. Using bone marrow transplantation and cell type-specific Casp3 knockout mice, we demonstrated that Casp3/GSDME-mediated pyroptosis in renal parenchymal cells, but not in hematopoietic cells, played predominant roles in this process. We further showed that HMGB1 released from pyroptotic RTCs amplified inflammatory responses, which critically contributed to renal fibrogenesis. Specific deletion of Hmgb1 in RTCs alleviated caspase11 and IL-1β activation in macrophages. Collectively, our results uncovered that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced renal tubule injury, which subsequentially contributes to the late-stage progression of hydronephrosis, inflammation, and fibrosis. This novel mechanism will provide valuable therapeutic insights for the treatment of obstructive nephropathy.
Topics: Animals; Disease Models, Animal; Fibrosis; Humans; Inflammation; Kidney Diseases; Mice; Pore Forming Cytotoxic Proteins; Pyroptosis
PubMed: 33664482
DOI: 10.1038/s41418-021-00755-6 -
Endocrinology and Metabolism Clinics of... Dec 2019Renovascular disease (RVD) is a major cause of secondary hypertension. Atherosclerotic renal artery stenosis is the most common type of RVD followed by fibromuscular... (Review)
Review
Renovascular disease (RVD) is a major cause of secondary hypertension. Atherosclerotic renal artery stenosis is the most common type of RVD followed by fibromuscular dysplasia. It has long been recognized as the prototype of angiotensin-dependent hypertension. However, the mechanisms underlying the physiopathology of hypertensive occlusive vascular renal disease are complex and distinction between the different causes of RVD should be made. Recognition of these distinct types of RVD with different degrees of renal occlusive disease is important for management. The greatest challenge is to individualize and implement the best approach for each patient in the setting of widely different comorbidities.
Topics: Fibromuscular Dysplasia; Humans; Hypertension, Renal; Hypertension, Renovascular; Nephritis; Renal Artery Obstruction
PubMed: 31655775
DOI: 10.1016/j.ecl.2019.08.007 -
Cell Death & Disease Aug 2022Renal fibrosis is a common consequence of various progressive nephropathies, including obstructive nephropathy, and ultimately leads to kidney failure. Infiltration of...
Renal fibrosis is a common consequence of various progressive nephropathies, including obstructive nephropathy, and ultimately leads to kidney failure. Infiltration of inflammatory cells is a prominent feature of renal injury after draining blockages from the kidney, and correlates closely with the development of renal fibrosis. However, the underlying molecular mechanism behind the promotion of renal fibrosis by inflammatory cells remains unclear. Herein, we showed that unilateral ureteral obstruction (UUO) induced Gasdermin D (GSDMD) activation in neutrophils, abundant neutrophil extracellular traps (NETs) formation and macrophage-to-myofibroblast transition (MMT) characterized by α-smooth muscle actin (α-SMA) expression in macrophages. Gsdmd deletion significantly reduced infiltration of inflammatory cells in the kidneys and inhibited NETs formation, MMT and thereby renal fibrosis. Chimera studies confirmed that Gsdmd deletion in bone marrow-derived cells, instead of renal parenchymal cells, provided protection against renal fibrosis. Further, specific deletion of Gsdmd in neutrophils instead of macrophages protected the kidney from undergoing fibrosis after UUO. Single-cell RNA sequencing identified robust crosstalk between neutrophils and macrophages. In vitro, GSDMD-dependent NETs triggered p65 translocation to the nucleus, which boosted the production of inflammatory cytokines and α-SMA expression in macrophages by activating TGF-β1/Smad pathway. In addition, we demonstrated that caspase-11, that could cleave GSDMD, was required for NETs formation and renal fibrosis after UUO. Collectively, our findings demonstrate that caspase-11/GSDMD-dependent NETs promote renal fibrosis by facilitating inflammation and MMT, therefore highlighting the role and mechanisms of NETs in renal fibrosis.
Topics: Caspases; Extracellular Traps; Fibrosis; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Diseases; Macrophages; Myofibroblasts; Phosphate-Binding Proteins; Pore Forming Cytotoxic Proteins; Signal Transduction; Ureteral Obstruction
PubMed: 35941120
DOI: 10.1038/s41419-022-05138-4 -
Nature Communications Mar 2023The functions of the influenza virus neuraminidase has been well documented but those of the mammalian neuraminidases remain less explored. Here, we characterize the...
The functions of the influenza virus neuraminidase has been well documented but those of the mammalian neuraminidases remain less explored. Here, we characterize the role of neuraminidase 1 (NEU1) in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models. We find that NEU1 is significantly upregulated in the fibrotic kidneys of patients and mice. Functionally, tubular epithelial cell-specific NEU1 knockout inhibits epithelial-to-mesenchymal transition, inflammatory cytokines production, and collagen deposition in mice. Conversely, NEU1 overexpression exacerbates progressive renal fibrosis. Mechanistically, NEU1 interacts with TGFβ type I receptor ALK5 at the 160-200aa region and stabilizes ALK5 leading to SMAD2/3 activation. Salvianolic acid B, a component of Salvia miltiorrhiza, is found to strongly bind to NEU1 and effectively protect mice from renal fibrosis in a NEU1-dependent manner. Collectively, this study characterizes a promotor role for NEU1 in renal fibrosis and suggests a potential avenue of targeting NEU1 to treat kidney diseases.
Topics: Animals; Male; Mice; Fibrosis; Gene Expression; Kidney; Kidney Diseases; Mice, Inbred C57BL; Neuraminidase; Ureteral Obstruction
PubMed: 36973294
DOI: 10.1038/s41467-023-37450-8 -
Nature Communications Oct 2022Renal fibrosis is an inevitable outcome of various manifestations of progressive chronic kidney diseases (CKD). The need for efficacious treatment regimen against renal...
Renal fibrosis is an inevitable outcome of various manifestations of progressive chronic kidney diseases (CKD). The need for efficacious treatment regimen against renal fibrosis can therefore not be overemphasized. Here we show a novel protective role of Bacteroides fragilis (B. fragilis) in renal fibrosis in mice. We demonstrate decreased abundance of B. fragilis in the feces of CKD patients and unilateral ureteral obstruction (UUO) mice. Oral administration of live B. fragilis attenuates renal fibrosis in UUO and adenine mice models. Increased lipopolysaccharide (LPS) levels are decreased after B. fragilis administration. Results of metabolomics and proteomics studies show decreased level of 1,5-anhydroglucitol (1,5-AG), a substrate of SGLT2, which increases after B. fragilis administration via enhancement of renal SGLT2 expression. 1,5-AG is an agonist of TGR5 that attenuates renal fibrosis by inhibiting oxidative stress and inflammation. Madecassoside, a natural product found via in vitro screening promotes B. fragilis growth and remarkably ameliorates renal fibrosis. Our findings reveal the ameliorative role of B. fragilis in renal fibrosis via decreasing LPS and increasing 1,5-AG levels.
Topics: Adenine; Animals; Bacteroides fragilis; Biological Products; Disease Models, Animal; Fibrosis; Gastrointestinal Microbiome; Kidney; Kidney Diseases; Lipopolysaccharides; Mice; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2; Ureteral Obstruction
PubMed: 36241632
DOI: 10.1038/s41467-022-33824-6 -
Cellular and Molecular Life Sciences :... Feb 2022Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important...
Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-β. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.
Topics: Animals; Fibrosis; Galectin 3; Humans; Kidney Diseases; Macrophage Activation; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Twist-Related Protein 1; Ureteral Obstruction
PubMed: 35182235
DOI: 10.1007/s00018-022-04137-0 -
Nature Communications Sep 2020Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy...
Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.
Topics: Aged; Animals; Apoptosis; Connective Tissue Growth Factor; Diabetic Nephropathies; Disease Models, Animal; Female; Fibrosis; Genetic Predisposition to Disease; Glutathione Transferase; HSP90 Heat-Shock Proteins; Humans; Inflammation; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Signal Transduction; Smad3 Protein; Tumor Suppressor Protein p53
PubMed: 32948751
DOI: 10.1038/s41467-020-18304-z -
American Journal of Kidney Diseases :... Aug 2020Diabetes is the leading cause of kidney failure worldwide, whereas glomerulonephritis has been predominant in developing countries such as China. The prevalence of... (Review)
Review
Diabetes is the leading cause of kidney failure worldwide, whereas glomerulonephritis has been predominant in developing countries such as China. The prevalence of obesity and diabetes has increased dramatically in developing countries, substantially affecting the patterns of chronic kidney disease (CKD) observed in these regions. Using data from the Hospital Quality Monitoring System to evaluate changes in the spectrum of non-dialysis-dependent CKD in China, we have observed an increase in the percentage of patients with CKD due to diabetes, which has exceeded that of CKD due to glomerulonephritis since 2011, as well as an increase in hypertensive nephropathy and, in some regions, obstructive kidney disease (mostly associated with kidney stones). The growth of noncommunicable diseases under profound societal and environmental changes has shifted the spectrum of CKD in China toward patterns similar to those of developed countries, which will have enormous impacts on the Chinese health care system. There is much to be done regarding public health interventions, including the establishment of a national CKD surveillance system, improvement in the management of diabetes and hypertension, and enhancement of the affordability and accessibility of kidney replacement therapy. Reducing the burden of CKD will require joint efforts from government, the medical community (including practitioners other than nephrologists), and the public.
Topics: China; Diabetes Mellitus; Diabetic Nephropathies; Glomerulonephritis; Humans; Hypertension; Kidney Calculi; Kidney Failure, Chronic; Obesity; Overweight; Public Health; Renal Insufficiency, Chronic; Renal Replacement Therapy
PubMed: 31492486
DOI: 10.1053/j.ajkd.2019.05.032 -
Advances in Clinical and Experimental... Feb 2022Anticoagulant-related nephropathy (ARN) is a novel and not well-studied cause of acute kidney injury (AKI). The prevalence of ARN varies significantly between studies... (Review)
Review
Anticoagulant-related nephropathy (ARN) is a novel and not well-studied cause of acute kidney injury (AKI). The prevalence of ARN varies significantly between studies and is estimated at 20% in patients treated with warfarin. Patients with ARN have a significantly higher mortality risk and an increased risk of chronic kidney disease (CKD). Unexplained AKI with hematuria are clinical manifestations of ARN. In most cases, ARN is diagnosed within the first 2 months of anticoagulant therapy, but later ARN occurrence is possible. Among the studied anticoagulants, most data concern warfarin toxicity, whereas cases of ARN caused by direct oral anticoagulants (DOACs) have also been presented. Tubular obstruction by red blood cell casts or hemoglobin and iron tubular toxicity are the postulated mechanisms of ARN. On the molecular level, the inhibition of thrombin and protease-activated receptor-1 (PAR-1), leading to endothelial susceptibility to damage or abnormal protein C endothelial signaling, is suggested to contribute to ARN. Older age, impaired kidney function, hypertension, and diabetes mellitus are the main risk factors for ARN, but their significance may differ between anticoagulants. From therapeutic options, the withdrawal of the anticoagulant and the administration of its antidote, as well as corticosteroids or N-acetylcysteine, are proposed. Since the number of patients with kidney diseases on anticoagulants increases, and DOACs are starting to be more useful in this group of patients, we aim to summarize the pathogenesis, clinical picture and possible ways of treatment of DOAC-induced ARN.
Topics: Acute Kidney Injury; Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Renal Insufficiency, Chronic; Rivaroxaban; Warfarin
PubMed: 35212199
DOI: 10.17219/acem/142657