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Annual Review of Physiology Feb 2024Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron.... (Review)
Review
Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption.
Topics: Humans; Kidney Tubules; Bartter Syndrome; Kearns-Sayre Syndrome; Kidney Diseases; Mitochondria
PubMed: 38012047
DOI: 10.1146/annurev-physiol-042222-025000 -
Redox Biology Dec 2023Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital...
Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital pathological factor in different types of metabolic diseases, such as DKD. Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor antagonist, attenuates kidney inflammation and fibrosis in DKD, but the precise pathomechanisms remain unclear. The role of mineralocorticoid receptor (MR) in perturbing mitochondrial function via the PI3K/Akt/eNOS signaling pathway, including mitochondrial dynamics and mitophagy, was investigated under a diabetic state and high glucose (HG) ambiance. To elucidate how the activation of MR provokes mitochondrial dysfunction in DT, human kidney proximal tubular epithelial (HK-2) cells were exposed to HG, and then mitochondrial dynamics, mitophagy, mitochondrial ROS (mitoROS), signaling molecules PI3K, Akt, Akt phosphorylation and eNOS were probed. The above molecules or proteins were also explored in the kidneys of diabetic and FIN-treated mice. FIN treatment reduced oxidative stress, mitochondrial fragmentation, and apoptosis while restoring the mitophagy via PI3K/Akt/eNOS signaling pathway in HK-2 cells exposed to HG ambiance and tubular cells of DM mice. These findings linked MR activation to mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in DT and highlight a pivotal but previously undiscovered role of FIN in alleviating renal tubule injury for the treatment of DKD.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins c-akt; Mineralocorticoid Receptor Antagonists; Phosphatidylinositol 3-Kinases; Signal Transduction; Diabetic Nephropathies; Mitochondria; Diabetes Mellitus
PubMed: 37924663
DOI: 10.1016/j.redox.2023.102946 -
Kidney International Dec 2023The efficient reabsorption of essential nutrients by epithelial cells in the proximal tubule of the kidney is crucial for maintaining homeostasis. This process relies... (Review)
Review
The efficient reabsorption of essential nutrients by epithelial cells in the proximal tubule of the kidney is crucial for maintaining homeostasis. This process relies heavily on a complex ecosystem of vesicular trafficking pathways. At the center of this network, the lysosome plays a pivotal role in processing incoming molecules, sensing nutrient availability, sorting receptors and transporters, and balancing differentiation and proliferation in the tubular epithelial cells. Disruptions in these fundamental processes can lead to proximal tubulopathy-a condition characterized by the dysfunction of the tubular cells followed by the presence of low-molecular-weight proteins and solutes in urine. If left untreated, proximal tubulopathy can progress to chronic kidney disease and severe complications. Functional studies of rare inherited disorders affecting the proximal tubule have gleaned actionable insights into fundamental mechanisms of homeostasis while revealing drug targets for therapeutic discovery and development. In this mini review, we explore hereditary proximal tubulopathies as a paradigm of kidney homeostasis disorders, discussing the factors contributing to tubular dysfunction. In addition, we shed light on the current landscape of drug discovery approaches used to identify actionable targets and summarize the preclinical pipeline of potential therapeutic agents. These efforts may ultimately lead to new treatment avenues for proximal tubulopathies, which are currently inadequately tackled by existing therapies. Through this article, our hope is to promote academia-industry partnerships and advocate for research consortia that can accelerate the effective translation of knowledge advances into innovative therapies addressing the huge unmet needs of individuals with these debilitating diseases.
Topics: Humans; Cell Differentiation; Drug Discovery; Kidney; Kidney Diseases
PubMed: 37783447
DOI: 10.1016/j.kint.2023.08.026 -
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 -
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 -
Kidney International Reports Aug 2023Lysozyme-associated nephropathy (LyN), a rare cause of kidney injury in patients with chronic myelomonocytic leukemia (CMML), has not been well described to date. We...
INTRODUCTION
Lysozyme-associated nephropathy (LyN), a rare cause of kidney injury in patients with chronic myelomonocytic leukemia (CMML), has not been well described to date. We report the clinicopathologic spectrum of LyN from a multi-institutional series.
METHOD
We identified 37 native kidney biopsies with LyN and retrospectively obtained clinicopathologic data.
RESULTS
Thirty-seven patients had a median age of 74 years and included 78% males. Their most common presentation was acute kidney injury (AKI) or AKI on chronic kidney disease (CKD) (66%) with median estimated glomerular filtration rate (eGFR) of 21.7 ml/min per 1.73 m, and proteinuria of 1.7 g. A minority (15%) had partial Fanconi syndrome. Serum lysozyme levels were elevated in all tested. Hematologic disorder ( = 28, 76%) was the most common etiology, including CMML ( = 15), acute myeloid leukemia ( = 5), and myelodysplastic syndrome (MDS) ( = 5). Nonhematologic causes ( = 5, 14%), included metastatic neuroendocrine carcinoma ( = 3), sarcoidosis, and leprosy. Etiology was unknown in 4 (11%). Pathology showed proximal tubulopathy with abundant hypereosinophilic intracytoplasmic inclusions, with characteristic staining pattern by lysozyme immunostain. Mortality was high (8/30). However, among the 22 alive, including 85% treated, 7 had improved kidney function, including 1 who discontinued dialysis and 6 with increase in eGFR >15 ml/min per 1.73 m compared with eGFR at the time of biopsy.
CONCLUSION
Increased awareness of the full clinicopathologic spectrum of LyN may lead to prompt diagnosis, earlier treatment, and potentially improved outcome of this rare entity.
PubMed: 37547521
DOI: 10.1016/j.ekir.2023.05.007 -
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 -
Internal Medicine (Tokyo, Japan) Mar 2024A 70-year-old woman with acute kidney injury, a high serum Creatinine (Cr) level (3.91 mg/dL), and proteinuria (protein/Cr ratio 1.59 g/gCr) was admitted. Serum IgG...
A 70-year-old woman with acute kidney injury, a high serum Creatinine (Cr) level (3.91 mg/dL), and proteinuria (protein/Cr ratio 1.59 g/gCr) was admitted. Serum IgG λ-type and urinary λ-type M proteins were observed. A bone marrow examination indicated monoclonal gammopathy of undetermined significance (MGUS). A renal biopsy showed distended proximal tubular cells, and immunofluorescence identified tissue positive for proximal tubular cell λ light chains. Electron microscopy identified fibril-like structures in the lysosomes. The patient was diagnosed with light chain proximal tubulopathy without crystals in IgG λ-type MGUS and treated with bortezomib and dexamethasone therapy, which improved her renal function.
Topics: Female; Humans; Aged; Bortezomib; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias; Kidney Diseases; Dexamethasone; Immunoglobulin G
PubMed: 37438138
DOI: 10.2169/internalmedicine.1835-23 -
Infection & Chemotherapy Jun 2023The incidence of tenofovir disoproxil fumarate (TDF)-induced nephrotoxicity ranges from 15.8 to 19.3 percent. Following cessation of TDF, approximately one-half of...
BACKGROUND
The incidence of tenofovir disoproxil fumarate (TDF)-induced nephrotoxicity ranges from 15.8 to 19.3 percent. Following cessation of TDF, approximately one-half of patients with nephrotoxicity regained full renal functions. This study aimed to determine the incidence and risk factors for nephrotoxicity, as well as the complete recovery of renal function, in human immunodeficiency virus (HIV)-infected patients receiving TDF regimens.
MATERIALS AND METHODS
This was a retrospective case-control study of HIV-positive patients who received TDF regimens from 2 tertiary hospitals between 2012 and 2018. Signs of TDF-induced renal dysfunction, defined as having estimated glomerular filtration rate (eGFR) decline of greater than 25%, and proximal renal tubulopathy (PRT) were followed for 48 months. After discontinuing TDF due to nephrotoxicity, the renal parameters of patients were monitored for 48 months. Univariate and multivariate regression analyses were used to determine the factors associated with TDF-induced nephrotoxicity and renal function recovery.
RESULTS
Twelve percent of 3,214 TDF-treated patients were diagnosed with renal dysfunction, whereas 303 patients (15.20%) were diagnosed with PRT. TDF-induced renal dysfunction was associated with older age (odds ratio [OR] = 2.851), smoking (OR = 1.972), and TDF use for more than 3 years (OR 1.928). Receiving trimethoprim-sulfamethoxazole (TMP/SMX) or nonsteroidal anti-inflammatory drugs (NSAIDs) and being elderly were associated with PRT (OR = 4.727, 4.313, and 3.357, respectively). Following the discontinuation of TDF, 12.96% of patients regained full renal function. Elderly patients and those taking renin-angiotensin-aldosterone system (RAAS) inhibitors or protease inhibitors (PIs) had a lower likelihood of full recovery (OR = 0.811, 0.793, 0.582, respectively). One-third experienced PRT recovery, whereas RAAS inhibitors use, old age, and receiving PIs decreased the likelihood of PRT recovery (OR = 0.709, 0.504, 0.311, respectively). TDF cessation at an eGFR greater than 60 mL/min/1.73 m² increased the likelihood of renal function recovery and PRT by 4.07 and 2.11 times, respectively.
CONCLUSION
Twelve percent and 15 percent of patients receiving TDF developed renal dysfunction and PRT, respectively. Age, TMP/SMX, NSAIDs, and long-term TDF exposure were independent risk factors for TDF-induced nephrotoxicity. Thirteen and thirty-three percent of patients with renal dysfunction and PRT recovered from their conditions, respectively. The discontinuation of TDF at an eGFR greater than 60 mL/min/1.73 m² was advantageous for the recovery of renal function and PRT.
PubMed: 37272235
DOI: 10.3947/ic.2023.0001