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American Journal of Physiology. Renal... Nov 2002Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of... (Review)
Review
Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.
Topics: Animals; Fibrosis; Humans; Kidney Diseases; Ureteral Obstruction
PubMed: 12372761
DOI: 10.1152/ajprenal.00362.2001 -
Scientific Reports Dec 2019Urinary tract obstruction during kidney development causes tubular apoptosis, tubular necrosis, and interstitial inflammation. Necroptosis is a subtype of programmed...
Urinary tract obstruction during kidney development causes tubular apoptosis, tubular necrosis, and interstitial inflammation. Necroptosis is a subtype of programmed necrosis mediated by the receptor-interacting serine/threonine-protein kinase-3 (RIPK3) and the pseudokinase mixed lineage kinase domain-like (MLKL). Necrosis induces inflammation and stimulates cell death in an autoamplification loop named necroinflammation. Here, we studied necroptosis and necroinflammation in obstructive nephropathy induced by unilateral ureteral obstruction (UUO) in neonatal C57Bl/6J mice. Ureteral obstruction induced tubular dilatation, tubular basement membrane thickening, cast formation, and increased expression of kidney injury molecule-1 (KIM-1). Morphological investigations showed either apoptotic or necrotic cells in the tubular compartment. Biochemical analysis revealed increased caspase-8 activity and upregulation of RIPK3 as well as phosphorylated-MLKL in UUO-kidneys. Pro-inflammatory cytokines (IL-1α, INF-γ, TNF-α) were upregulated following UUO. Taken together we show that necroptosis and necroinflammation are accompanied phenomena in neonatal kidneys with obstruction. These findings may help to develop novel strategies to treat congenital obstructive nephropathy.
Topics: Animals; Animals, Newborn; Apoptosis; Cytokines; Inflammation; Kidney; Kidney Diseases; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Necroptosis; Phosphorylation; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 31819111
DOI: 10.1038/s41598-019-55079-w -
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 -
Journal of Cellular and Molecular... Aug 2019Obstructive nephropathy is the end result of a variety of diseases that block drainage from the kidney(s). Transforming growth factor-β1 (TGF-β1)/Smad3-driven renal...
Obstructive nephropathy is the end result of a variety of diseases that block drainage from the kidney(s). Transforming growth factor-β1 (TGF-β1)/Smad3-driven renal fibrosis is the common pathogenesis of obstructive nephropathy. In this study, we identified petchiether A (petA), a novel small-molecule meroterpenoid from Ganoderma, as a potential inhibitor of TGF-β1-induced Smad3 phosphorylation. The obstructive nephropathy was induced by unilateral ureteral obstruction (UUO) in mice. Mice received an intraperitoneal injection of petA/vehicle before and after UUO or sham operation. An in vivo study revealed that petA protected against renal inflammation and fibrosis by reducing the infiltration of macrophages, inhibiting the expression of proinflammatory cytokines (interleukin-1β and tumour necrosis factor-α) and reducing extracellular matrix deposition (α-smooth muscle actin, collagen I and fibronectin) in the obstructed kidney of UUO mice; these changes were associated with suppression of Smad3 and NF-κB p65 phosphorylation. Petchiether A inhibited Smad3 phosphorylation in vitro and down-regulated the expression of the fibrotic marker collagen I in TGF-β1-treated renal epithelial cells. Further, we found that petA dose-dependently suppressed Smad3-responsive promoter activity, indicating that petA inhibits gene expression downstream of the TGF-β/Smad3 signalling pathway. In conclusion, our findings suggest that petA protects against renal inflammation and fibrosis by selectively inhibiting TGF-β/Smad3 signalling.
Topics: Actins; Animals; Cell Line; Collagen; Fibronectins; Fibrosis; Humans; Inflammation; Kidney; Kidney Diseases; Male; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Signal Transduction; Smad3 Protein; Terpenes; Transforming Growth Factor beta; Ureteral Obstruction
PubMed: 31211499
DOI: 10.1111/jcmm.14454 -
The Journal of Antimicrobial... Jan 2020Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and... (Review)
Review
Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and mortality in both children and adults. Antimicrobials are one of the most common classes of medications prescribed globally and also among the most common causes of nephrotoxicity. A broad range of antimicrobial agents have been associated with nephrotoxicity, but the features of kidney injury vary based on the agent, its mechanism of injury and the site of toxicity within the kidney. Distinguishing nephrotoxicity caused by an antimicrobial agent from other potential inciting factors is important to facilitate both early recognition of drug toxicity and prompt cessation of an offending drug, as well as to avoid unnecessary discontinuation of an innocuous therapy. This review will detail the different types of antimicrobial-induced nephrotoxicity: acute tubular necrosis, acute interstitial nephritis and obstructive nephropathy. It will also describe the mechanism of injury caused by specific antimicrobial agents and classes (vancomycin, aminoglycosides, polymyxins, antivirals, amphotericin B), highlight the toxicodynamics of these drugs and provide guidance on administration or monitoring practices that can mitigate toxicity, when known. Particular attention will be paid to paediatric patients, when applicable, in whom nephrotoxin exposure is an often-underappreciated cause of kidney injury.
Topics: Acute Kidney Injury; Anti-Infective Agents; Child; Humans; Kidney; Kidney Diseases; Nephritis, Interstitial
PubMed: 31369087
DOI: 10.1093/jac/dkz325 -
Kidney360 Nov 2021Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder.
BACKGROUND
Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder.
METHODS
Mice with targeted disruption of the molybdenum cofactor sulfurase () gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism.
RESULTS
-deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm-Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology.
CONCLUSIONS
-deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis.
Topics: Animals; Kidney Diseases; Mice; Purine-Pyrimidine Metabolism, Inborn Errors; Urolithiasis; Xanthine; Xanthine Dehydrogenase
PubMed: 35372998
DOI: 10.34067/KID.0001732021 -
Kidney International Jan 2017The antiphospholipid syndrome is a common autoimmune disease caused by pathogenic antiphospholipid antibodies, leading to recurrent thrombosis and/or obstetrical... (Review)
Review
The antiphospholipid syndrome is a common autoimmune disease caused by pathogenic antiphospholipid antibodies, leading to recurrent thrombosis and/or obstetrical complications. Importantly for nephrologists, antiphospholipid antibodies are associated with various renal manifestations including large renal vessel thrombosis, renal artery stenosis, and a constellation of intrarenal lesions that has been termed antiphospholipid nephropathy. This last condition associates various degrees of acute thrombotic microangiopathy, proliferative and fibrotic lesions of the intrarenal vessels, and ischemic modifications of the renal parenchyma. The course of the disease can range from indolent nephropathy to devastating acute renal failure. The pejorative impact of antiphospholipid antibody-related renal complication is well established in the context of systemic lupus erythematous or after renal transplantation. In contrast, the exact significance of isolated antiphospholipid nephropathy remains uncertain. The evidence to guide management of the renal complications of antiphospholipid syndrome is limited. However, the recent recognition of the heterogeneous molecular mechanisms underlying the progression of intrarenal vascular lesions in antiphospholipid syndrome have opened promising tracks for patient monitoring and targeted therapeutic intervention.
Topics: Allografts; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Antiphospholipid; Anticoagulants; Antiphospholipid Syndrome; Disease Progression; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Magnetic Resonance Imaging; Plasma Exchange; Renal Artery Obstruction; Thrombosis; beta 2-Glycoprotein I
PubMed: 27555120
DOI: 10.1016/j.kint.2016.06.026 -
Acta Pharmacologica Sinica Nov 2022Nucleotide-binding oligomerization domain-like receptors (NLRs), including NLRAs, NLRBs (also known as NAIPs), NLRCs, and NLRPs, are a major subfamily of pattern... (Review)
Review
Nucleotide-binding oligomerization domain-like receptors (NLRs), including NLRAs, NLRBs (also known as NAIPs), NLRCs, and NLRPs, are a major subfamily of pattern recognition receptors (PRRs). Owing to a recent surge in research, NLRs have gained considerable attention due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, which is a central phenomenon in the pathogenesis of multiple diseases, including renal diseases. NLRs are expressed in different renal tissues during pathological conditions, which suggest that these receptors play roles in acute kidney injury, obstructive nephropathy, diabetic nephropathy, IgA nephropathy, lupus nephritis, crystal nephropathy, uric acid nephropathy, and renal cell carcinoma, among others. This review summarises recent progress on the functions of NLRs and their mechanisms in the pathophysiological processes of different types of renal diseases to help us better understand the role of NLRs in the kidney and provide a theoretical basis for NLR-targeted therapy for renal diseases.
Topics: Humans; NLR Proteins; Immunity, Innate; Diabetic Nephropathies; Kidney; Carrier Proteins
PubMed: 35365780
DOI: 10.1038/s41401-022-00886-7 -
Cell Stress & Chaperones Nov 2015Urinary heat shock protein 70 (Hsp70) is rapidly increased in patients with clinical acute kidney injury, indicating that it constitutes a component of the endogenous... (Review)
Review
Urinary heat shock protein 70 (Hsp70) is rapidly increased in patients with clinical acute kidney injury, indicating that it constitutes a component of the endogenous stress response to renal injury. Moreover, experimental models have demonstrated that Hsp70 activation is associated with the cytoprotective actions of several drugs following obstruction, including nitric oxide (NO) donors, geranylgeranylacetone, vitamin D, and rosuvastatin. Discrete and synergistic effects of the biological activities of Hsp70 may explain its cytoprotective role in obstructive nephropathy. Basic studies point to a combination of effects including inhibition of apoptosis and inflammation, repair of damaged proteins, prevention of unfolded protein aggregation, targeting of damaged protein for degradation, and cytoskeletal stabilization as primary effectors of Hsp70 action. This review summarizes our understanding of how the biological actions of Hsp70 may affect renal cytoprotection in the context of obstructive injury. The potential of Hsp70 to be of central importance to the mechanism of action of various drugs that modify the genesis of experimental obstructive nephropathy is considered.
Topics: Animals; Apoptosis; HSP70 Heat-Shock Proteins; Humans; Inflammation; Kidney Diseases; Nitric Oxide; Ureteral Obstruction
PubMed: 26228633
DOI: 10.1007/s12192-015-0622-z -
Journal of Cellular and Molecular... May 2023Chronic kidney diseases affect a substantial percentage of the adult population worldwide. This observation emphasizes the need for novel insights into the molecular...
Chronic kidney diseases affect a substantial percentage of the adult population worldwide. This observation emphasizes the need for novel insights into the molecular mechanisms that control the onset and progression of renal diseases. Recent advances in genomics have uncovered a previously unanticipated link between the non-coding genome and human kidney diseases. Here we screened and analysed long non-coding RNAs (lncRNAs) previously identified in mouse kidneys by genome-wide transcriptomic analysis, for conservation in humans and differential expression in renal tissue from healthy and diseased individuals. Our data suggest that LINC01187 is strongly down-regulated in human kidney tissues of patients with diabetic nephropathy and rapidly progressive glomerulonephritis, as well as in murine models of kidney diseases, including unilateral ureteral obstruction, nephrotoxic serum-induced glomerulonephritis and ischemia/reperfusion. Interestingly, LINC01187 overexpression in human kidney cells in vitro inhibits cell death indicating an anti-apoptotic function. Collectively, these data suggest a negative association of LINC01187 expression with renal diseases implying a potential protective role.
Topics: Animals; Humans; Mice; Diabetic Nephropathies; Down-Regulation; Glomerulonephritis; Kidney; RNA, Long Noncoding
PubMed: 37056054
DOI: 10.1111/jcmm.17014