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Cells Dec 2022Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed... (Review)
Review
Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed to an extensive amount of nutrients, most notably glucose; these nutrients deteriorate KPTCs function and promote the development and progression of DKD. Recently, the facilitative glucose transporter 2 (GLUT2) in KPTCs has emerged as a central regulator in the pathogenesis of DKD. This has been demonstrated by identifying its specific role in enhancing glucose reabsorption and glucotoxicity, and by deciphering its effect in regulating the expression of the sodium-glucose transporter 2 (SGLT2) in KPTCs. Moreover, reduction/deletion of KPTC-GLUT2 has been recently found to ameliorate DKD, raising the plausible idea of considering it as a therapeutic target against DKD. However, the underlying molecular mechanisms by which GLUT2 exerts its deleterious effects in KPTCs remain vague. Herein, we review the current findings on the proximal tubule GLUT2 biology and function under physiologic conditions, and its involvement in the pathophysiology of DKD. Furthermore, we shed new light on its cellular regulation during diabetic conditions.
Topics: Humans; Kidney; Kidney Tubules, Proximal; Glucose; Diabetic Nephropathies; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 36611887
DOI: 10.3390/cells12010094 -
Ophthalmic Genetics Dec 2023The genetic tubulopathies are rare and heterogenous disorders that are often difficult to identify. This study examined the tubulopathy-causing genes for ocular... (Review)
Review
BACKGROUND
The genetic tubulopathies are rare and heterogenous disorders that are often difficult to identify. This study examined the tubulopathy-causing genes for ocular associations that suggested their genetic basis and, in some cases, the affected gene.
METHODS
Sixty-seven genes from the Genomics England renal tubulopathy panel were reviewed for ocular features, and for retinal expression in the Human Protein Atlas and an ocular phenotype in mouse models in the Mouse Genome Informatics database. The genes resulted in disease affecting the proximal tubules ( = 24); the thick ascending limb of the loop of Henle ( = 10); the distal convoluted tubule ( = 15); or the collecting duct ( = 18).
RESULTS
Twenty-five of the tubulopathy-associated genes (37%) had ocular features reported in human disease, 49 (73%) were expressed in the retina, although often at low levels, and 16 (24%) of the corresponding mouse models had an ocular phenotype. Ocular abnormalities were more common in genes affected in the proximal tubulopathies (17/24, 71%) than elsewhere (7/43, 16%). They included structural features (coloboma, microphthalmia); refractive errors (myopia, astigmatism); crystal deposition (in oxalosis, cystinosis) and sclerochoroidal calcification (in Bartter, Gitelman syndromes). Retinal atrophy was common in the mitochondrial-associated tubulopathies. Structural abnormalities and crystal deposition were present from childhood, but sclerochoroidal calcification typically occurred after middle age.
CONCLUSIONS
Ocular abnormalities are uncommon in the genetic tubulopathies but may be helpful in recognizing the underlying genetic disease. The retinal expression and mouse phenotype data suggest that further ocular associations may become apparent with additional reports. Early identification may be necessary to monitor and treat visual complications.
Topics: Middle Aged; Humans; Animals; Mice; Child; Face; Retina; Astigmatism; Myopia; Refractive Errors; Calcinosis; Disease Models, Animal
PubMed: 37702059
DOI: 10.1080/13816810.2023.2253901 -
Advances in Anatomic Pathology Mar 2015Monoclonal gammopathy is produced by neoplastic or non-neoplastic expansion of a clone of plasma cells or B lymphocytes. Monoclonal gammopathy of unknown significance is... (Review)
Review
Monoclonal gammopathy is produced by neoplastic or non-neoplastic expansion of a clone of plasma cells or B lymphocytes. Monoclonal gammopathy of unknown significance is characterized by low levels of the monoclonal protein and a relatively small population of clonal lymphocytes or plasma cells in the bone marrow. In these cases, the patient is asymptomatic with no evidence of overt myeloma or lymphoma. The abnormal serum protein may be present as a complete immunoglobulin molecule or may consist of ≥1 of its components such as light chains or heavy chains. These proteins may cause a variety of diseases in various tissues and organs, of which the kidney appears to be the most vulnerable. Renal involvement in monoclonal gammopathy may occur as part of a generalized disease such as amyloidosis, immunoglobulin deposition disease, and cryoglobulinemia. In addition, there may be evidence of kidney damage by processes which are renal specific. These include light chain proximal tubulopathy, light chain cast nephropathy, and a variety of glomerulopathies encompassing a wide spectrum of disease patterns.
Topics: Amyloidosis; Humans; Immunoglobulins; Kidney; Kidney Diseases; Paraproteinemias
PubMed: 25664947
DOI: 10.1097/PAP.0000000000000056 -
World Journal of Nephrology Jan 2017Dent's disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is... (Review)
Review
Dent's disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is associated with mutations in the gene coding for the electrogenic 2Cl/H antiporter chloride channel 5 (CLC-5), which is expressed in the apical endosomes of renal proximal tubules with the vacuolar type H-ATPase (V-ATPase). Initially identified as a member of the CLC family of Cl channels, CLC-5 was presumed to provide Cl shunt into the endosomal lumen to dissipate H accumulation by V-ATPase, thereby facilitating efficient endosomal acidification. However, recent findings showing that CLC-5 is in fact not a Cl channel but a 2Cl/H antiporter challenged this classical shunt model, leading to a renewed and intense debate on its physiological roles. Cl accumulation CLC-5 is predicted to play a critical role in endocytosis, as illustrated in mice carrying an artificial Cl channel mutation E211A that developed defective endocytosis but normal endosomal acidification. Conversely, a recent functional analysis of a newly identified disease-causing Cl channel mutation E211Q in a patient with typical Dent's disease confirmed the functional coupling between V-ATPase and CLC-5 in endosomal acidification, lending support to the classical shunt model. In this editorial, we will address the current recognition of the physiological role of CLC-5 with a specific focus on the functional coupling of V-ATPase and CLC-5.
PubMed: 28101447
DOI: 10.5527/wjn.v6.i1.14 -
Revista Espanola de Patologia :... 2022The kidney is one of the organs most frequently affected by disease processes which produce monoclonal immunoglobins, therefore renal morphological and...
INTRODUCTION
The kidney is one of the organs most frequently affected by disease processes which produce monoclonal immunoglobins, therefore renal morphological and immunopathological alterations should be clearly recognized.
OBJECTIVE
To describe the pathological features of renal involvement in monoclonal gammopathies.
MATERIAL AND METHODS
A descriptive, retrospective and cross-sectional study of renal biopsies studied in a single center during a period of 14 years was carried out.
RESULTS
102 cases were included, of which 53% were male patients and the median age was 62.5 years (range 34 - 79). 97% of the biopsies were from native kidneys. The most frequent histopathological diagnosis (31.4%) was myeloma kidney, with kappa being the light chain most frequently deposited (65.6% of cases). AL amyloidosis was the second most common (29.4%) where the lambda chain predominated in 86.6%, followed by light chain deposition disease (20.6%) with the predominance of the kappa chain in 66.6%.
CONCLUSIONS
The most frequent renal involvement due to monoclonal gammopathies was myeloma kidney with deposition of kappa light chains, followed by AL lambda amyloidosis; these diseases were found more frequently in patients over 50 years of age.
Topics: Adult; Aged; Cross-Sectional Studies; Humans; Kidney Diseases; Male; Middle Aged; Multiple Myeloma; Paraproteinemias; Retrospective Studies
PubMed: 34980439
DOI: 10.1016/j.patol.2021.06.002 -
Phytomedicine : International Journal... Oct 2023Diabetic kidney disease (DKD) is one of the major chronic microvascular complications of diabetes and the main cause of end-stage renal failure. Zhenwu Decoction (ZWD),...
BACKGROUND
Diabetic kidney disease (DKD) is one of the major chronic microvascular complications of diabetes and the main cause of end-stage renal failure. Zhenwu Decoction (ZWD), an ancient classic herbal formula in Chinese medicine, has been clinically used for the treatment of kidney disease in China for many years. However, there is currently limited research investigating the application of ZWD in the treatment of DKD and the underlying chemical and biochemical mechanisms involved. Therefore, in the present study, we aimed to identify active components in ZWD and unravel the possible mechanism(s) of action for ZWD in treating DKD.
METHODS
The protective effect of ZWD against DKD was evaluated utilizing an in vitro model of diabetic renal proximal tubulopathy. The major chemical components from ZWD were identified by LC-MS/MS. Drug targets were predicted by submitting the SMILES (Simplified Molecular Input Line Entry System) of the compounds to SEA (Similarity Ensemble Approach) search server and SwissTargetPrediction. The differentially expressed genes (DEGs) of the disease were collected and integrated from GeneCards. The constructions of "Compounds-potential targets interaction" (CTI) network and Protein-Protein Interaction (PPI) network, as well as topology analysis were conducted by Cytoscape. Gene Ontology (GO) enrichment and Metacore pathway enrichment analysis were also performed. Lastly, molecular docking and experimental studies were adopted to validate the core target and identify an active component(s) of ZWD.
RESULTS
We demonstrated that the ZWD extract could significantly rescue the palmitic acid (PA) and high glucose-induced apoptotic cell death in HK-2 cells, and the cytoprotection was accompanied by decreases in the extent of reactive oxygen species (ROS) production, mitochondrial membrane depolarization and ATP depletion. Fifty-seven compounds in the aqueous extract of ZWD were identified by LC-MS. The results of PPI analysis showed that top hub genes involved epidermal growth factor receptor (EGFR), Signal Transducer and Activator of Transcription 3 (STAT3), Serine/Threonine Kinase 1 (AKT1), Vascular Endothelial Growth Factor A (VEGFA) and Fibroblast Growth Factor 2 (FGF2). Pathway enrichment analysis revealed the involvement of S1P1 receptor signaling and EGFR pathways. The results of molecular docking analysis showed that albiflorin has a high binding affinity to EGFR. Albiflorin could also exert protective effects in an HK-2 cell model of DKD, which may be related to the inhibition of the high glucose/high lipid-induced EGFR and Akt phosphorylation.
CONCLUSION
ZWD has been shown to be effective in ameliorating cell death in an experimental model of DKD. The beneficial effect of ZWD against DKD was associated with the interactions between the active ingredients and the hub genes, such as EGFR, STAT3, AKT1, and VEGF-A. Albiflorin may be one of the active components responsible for the nephroprotective effect in ZWD.
Topics: Humans; Diabetic Nephropathies; Vascular Endothelial Growth Factor A; Chromatography, Liquid; Molecular Docking Simulation; Tandem Mass Spectrometry; Drugs, Chinese Herbal; ErbB Receptors; Diabetes Mellitus
PubMed: 37523837
DOI: 10.1016/j.phymed.2023.154988 -
Pediatric Nephrology (Berlin, Germany) Oct 2017Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in... (Review)
Review
BACKGROUND
Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in tubular proteinuria compared with glomerular disease. Several authors have reported nephrotic-range proteinuria (NP) and glomerulosclerosis in Dent disease. Therefore, we aimed to analyze protein excretion in patients with documented CLCN5 or OCRL mutations in a systematic literature review.
DESIGN
PubMed and Embase were searched for cases with documented CLCN5 or OCRL mutations and (semi-)quantitative data on protein excretion. The most reliable data (i.e., TPE > protein-creatinine ratio > Albustix) was used for NP classification.
RESULTS
Data were available on 148 patients from 47 reports: 126 had a CLCN5 and 22 an OCRLmutation. TPE was not significantly different between both forms (p = 0.11). Fifty-five of 126 (43.7 %) Dent-1 vs 13/22 (59.1 %) Dent-2 patients met the definition of NP (p = 0.25). Serum albumin was normal in all reported cases (24/148). Glomerulosclerosis was noted in 20/32 kidney biopsies and was strongly related to tubulointerstitial fibrosis, but not to kidney function or proteinuria.
CONCLUSION
More than half of the patients with both forms of Dent disease have NP, and the presence of low molecular weight proteinuria in a patient with NP in the absence of edema and hypoalbuminemia should prompt genetic testing. Even with normal renal function, glomerulosclerosis and tubulointerstitial fibrosis are present in Dent disease. The role of proteinuria in the course of the disease needs to be examined further in longitudinal studies.
Topics: Biopsy; Chloride Channels; Dent Disease; Genetic Testing; Humans; Kidney; Mutation; Nephritis, Interstitial; Phosphoric Monoester Hydrolases; Proteinuria; Renal Elimination; Serum Albumin
PubMed: 27757584
DOI: 10.1007/s00467-016-3499-x -
Journal of the American Society of... Mar 2018Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular... (Review)
Review
Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle's loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Antigens, Neoplasm; Bartter Syndrome; Child; Child, Preschool; Fanconi Syndrome; Gitelman Syndrome; Humans; Infant; Infant, Newborn; Kidney Tubules; Renal Reabsorption; Sodium Chloride; Solute Carrier Proteins
PubMed: 29237739
DOI: 10.1681/ASN.2017060600 -
Vnitrni Lekarstvi 2022One of the common causes of acute kidney injury (AKI) is drug nephrotoxicity. A large group of drugs associated with AKI includes a considerable number of...
One of the common causes of acute kidney injury (AKI) is drug nephrotoxicity. A large group of drugs associated with AKI includes a considerable number of antimicrobials. Clinical manifestations range from mild forms of tubular damage to significant deterioration of renal function requiring renal replacement therapy. Several mechanisms have been described, although the most common are acute interstitial nephritis, acute tubular necrosis, crystalic nephropathy or proximal/distal tubulopathy with electrolyte abnormalities. General risk factors for antimicrobial-induced AKI include pre-existing chronic kidney disease and concomitant use of drugs with nephrotoxic potential. Prevention and early recognition of AKI are the standard approach to mitigate AKI and avoid morbidity.
Topics: Acute Kidney Injury; Anti-Bacterial Agents; Electrolytes; Humans; Kidney; Nephritis, Interstitial; Renal Insufficiency, Chronic
PubMed: 36220420
DOI: No ID Found -
Journal of the American Society of... Nov 2023Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the...
SIGNIFICANCE STATEMENT
Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the diagnostic workup of patients with electrolyte disorders. In this systematic review, we investigated the presence of electrolyte disorders in patients with mitochondrial cytopathies to determine the relevance of mitochondrial mutation screening in this population. Our analysis demonstrates that electrolyte disorders are commonly reported in mitochondrial cytopathies, often as presenting symptoms. Consequently, more clinical attention should be raised for mitochondrial disease as cause for disturbances in electrolyte homeostasis. Further prospective cohort studies are required to determine the exact prevalence of electrolyte disorders in mitochondrial cytopathies.
BACKGROUND
Electrolyte reabsorption in the kidney has a high energy demand. Proximal and distal tubular epithelial cells have a high mitochondrial density for energy release. Recently, electrolyte disorders have been reported as the primary presentation of some mitochondrial cytopathies. However, the prevalence and the pathophysiology of electrolyte disturbances in mitochondrial disease are unknown. Therefore, we systematically investigated electrolyte disorders in patients with mitochondrial cytopathies.
METHODS
We searched PubMed, Embase, and Google Scholar for articles on genetically confirmed mitochondrial disease in patients for whom at least one electrolyte is reported. Patients with a known second genetic anomaly were excluded. We evaluated 214 case series and reports (362 patients) as well as nine observational studies. Joanna Briggs Institute criteria were used to evaluate the quality of included studies.
RESULTS
Of 362 reported patients, 289 had an electrolyte disorder, with it being the presenting or main symptom in 38 patients. The average number of different electrolyte abnormalities per patient ranged from 2.4 to 1.0, depending on genotype. Patients with mitochondrial DNA structural variants seemed most affected. Reported pathophysiologic mechanisms included renal tubulopathies and hormonal, gastrointestinal, and iatrogenic causes.
CONCLUSIONS
Mitochondrial diseases should be considered in the evaluation of unexplained electrolyte disorders. Furthermore, clinicians should be aware of electrolyte abnormalities in patients with mitochondrial disease.
Topics: Humans; Mitochondrial Myopathies; Kearns-Sayre Syndrome; Mitochondrial Diseases; Mitochondria; DNA, Mitochondrial; Water-Electrolyte Imbalance
PubMed: 37678265
DOI: 10.1681/ASN.0000000000000224