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ELife Feb 2023Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and...
Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and function under harsh hyperosmotic stress remains unclear. Using RNA-Seq, we identified SLC38A2 as a novel osmoresponsive neutral amino acid transporter in MCD cells. Hyperosmotic stress-induced cell death in MCD cells occurred mainly via ferroptosis, and it was significantly attenuated by SLC38A2 overexpression but worsened by -gene deletion or silencing. Mechanistic studies revealed that the osmoprotective effect of SLC38A2 is dependent on the activation of mTORC1. Moreover, an in vivo study demonstrated that -knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that is an important osmoresponsive gene in the renal medulla and provide novel insights into the critical role of SLC38A2 in protecting MCD cells from hyperosmolarity-induced ferroptosis via the mTORC1 signalling pathway.
Topics: Animals; Mice; Amino Acid Transport Systems, Neutral; Ferroptosis; Kidney; Kidney Medulla; Mechanistic Target of Rapamycin Complex 1
PubMed: 36722887
DOI: 10.7554/eLife.80647 -
International Journal of Molecular... Jul 2019Brain natriuretic peptide (BNP) is an important biomarker for patients with heart failure, hypertension and cardiac hypertrophy. Although it is known that BNP levels are... (Review)
Review
Brain natriuretic peptide (BNP) is an important biomarker for patients with heart failure, hypertension and cardiac hypertrophy. Although it is known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease, the mechanism remains unknown. Here, we review the functions and the roles of BNP in the heart-kidney interaction. In addition, we discuss the relevant molecular mechanisms that suggest BNP is protective against chronic kidney diseases and heart failure, especially in terms of the counterparts of the renin-angiotensin-aldosterone system (RAAS). The renal medulla has been reported to express depressor substances. The extract of the papillary tips from kidneys may induce the expression and secretion of BNP from cardiomyocytes. A better understanding of these processes will help accelerate pharmacological treatments for heart-kidney disease.
Topics: Angiotensin Receptor Antagonists; Animals; Disease Susceptibility; Gene Expression Regulation; Heart; Humans; Kidney; Myocytes, Cardiac; Natriuretic Peptide, Brain; Neprilysin; Renin-Angiotensin System; Signal Transduction; Vasoconstrictor Agents
PubMed: 31336656
DOI: 10.3390/ijms20143581 -
Seminars in Nephrology Nov 2019Renal tissue hypoxia has been implicated as a critical mediatory factor in multiple forms of acute kidney injury (AKI), including in sepsis. In sepsis, whole-kidney... (Review)
Review
Renal tissue hypoxia has been implicated as a critical mediatory factor in multiple forms of acute kidney injury (AKI), including in sepsis. In sepsis, whole-kidney measures of macrocirculatory flow and oxygen delivery appear to be poor predictors of microcirculatory abnormalities. Studies in experimental hyperdynamic septic AKI have shown that the renal medulla is particularly susceptible to hypoxia early in sepsis, even in the presence of increased global renal blood flow and oxygen delivery. It has been proposed that an early onset of progressive renal medullary hypoxia, leading to oxidative stress and inflammation, can initiate a downward spiral of cellular injury culminating in AKI. Recent experimental studies have shown that clinical therapies for septic AKI, including, fluids, vasopressors, and diuretics, have distinct effects on renal macrocirculation and microcirculation. Herein, we review the clinical and experimental evidence of alterations in global and regional kidney perfusion and oxygenation during septic AKI and associated therapies. We justify the need for investigation of the effects of therapies on renal microcirculatory perfusion and oxygenation. We propose that interventions that do not worsen the underlying renal pathophysiologic and reparative processes in sepsis will reduce the development and/or progression of AKI more effectively.
Topics: Acute Kidney Injury; Animals; Disease Management; Diuretics; Fluid Therapy; Humans; Hyperbaric Oxygenation; Kidney Medulla; Microcirculation; Oxidative Stress; Renal Circulation; Sepsis; Vasoconstrictor Agents
PubMed: 31836037
DOI: 10.1016/j.semnephrol.2019.10.004 -
Nephrology (Carlton, Vic.) Feb 2020The presence of the peritubular capillaritis and its extent are important for diagnosis of the antibody-mediated rejection in kidneys. However, it is recommended that...
OBJECTIVES
The presence of the peritubular capillaritis and its extent are important for diagnosis of the antibody-mediated rejection in kidneys. However, it is recommended that peritubular capillaritis should only be scored in the cortex. This study aims to focus on peritubular capillaritis scoring both in the cortex and the medulla to understand the value of the medulla in the diagnosis of antibody-mediated rejection.
METHODS
Fifty-one allograft renal biopsy were re-evaluated for peritubular capillaritis, C4d and acute tubular injury, separately for the cortex and the medulla according to the Banff.
RESULTS
Seventeen cases (33.3%) had peritubular capillaritis both in the cortex and the medulla and three (5.9%) cases had peritubular capillaritis only in the cortex while five (9.8%) cases had only in the medulla. Eighteen (35%) of the cases had C4d staining both in the cortex and the medulla and 14 (27.5%) cases had C4d positivity only in the cortex and 18 (35.3%) cases only in the medulla. Twenty-three (45%) cases had acute tubular injury both in the cortex and the medulla and 31 (60.7%) cases had acute tubular injury only in the cortex and 23 (45.1%) cases had only in the medulla. The sensitivity, specificity, positive and negative predictive values of medullar peritubular capillaritis predicting cortical peritubular capillaritis were 85.7%, 86.7%, 81.8% and 89.7%, respectively.
CONCLUSION
In case of absence of the cortical tissue, medulla can be used as a reference for antibody-mediated rejection considering the morphological features, results of donor-specific antibody and renal function tests.
Topics: Adult; Biopsy; Capillaries; Complement C4b; Female; Graft Rejection; Humans; Kidney Cortex; Kidney Transplantation; Kidney Tubules, Distal; Male; Reproducibility of Results; Sensitivity and Specificity; Transplantation Immunology
PubMed: 31074544
DOI: 10.1111/nep.13598 -
Nephron 2020Understanding and measuring parameters responsible for the pathogenesis of sepsis-induced AKI (SI-AKI) is critical in developing therapies. Blood flow to the kidney is... (Review)
Review
Understanding and measuring parameters responsible for the pathogenesis of sepsis-induced AKI (SI-AKI) is critical in developing therapies. Blood flow to the kidney is heterogeneous, partly due to the existence of dynamic networks of capillaries in various regions, responding differentially to oxygen demand in cortex versus medulla. High energy demand regions, especially the outer medulla, are susceptible to hypoxia and subject to damage during SI-AKI. Proximal tubule epithelial cells in the cortex and the outer medulla can also undergo metabolic reprogramming during SI-AKI to maintain basal physiological status and to avoid potential damage. Current data on the assessment of renal hemodynamics and oxygen metabolism during sepsis is limited. Preclinical and clinical studies show changes in renal hemodynamics associated with SI-AKI, and in clinical settings, interventions to manage renal hemodynamics seem to help improve disease outcomes in some cases. Lack of proper tools to assess temporospatial changes in peritubular blood flow and tissue oxygen metabolism is a barrier to our ability to understand microcirculatory dynamics and oxygen consumption and their role in the pathogenesis of SI-AKI. Current tools to assess renal oxygenation are limited in their usability as these cannot perform continuous simultaneous measurement of renal hemodynamics and oxygen metabolism. Multi-parametric photo-acoustic microscopy (PAM) is a new tool that can measure real-time changes in microhemodynamics and oxygen metabolism. Use of multi-parametric PAM in combination with advanced intravital imaging techniques has the potential to understand the contribution of microhemodynamic and tissue oxygenation alterations to SI-AKI.
Topics: Acute Kidney Injury; Animals; Capillaries; Disease Models, Animal; Humans; Iron; Oxygen Consumption; Sepsis
PubMed: 33147592
DOI: 10.1159/000511167 -
Proceedings of SPIE--the International... 2022Phantoms are invaluable tools broadly used for research and training purposes designed to mimic tissues and structures in the body. In this paper, polyvinyl chloride...
Phantoms are invaluable tools broadly used for research and training purposes designed to mimic tissues and structures in the body. In this paper, polyvinyl chloride (PVC)-plasticizer and silicone rubbers were explored as economical materials to reliably create long-lasting, realistic kidney phantoms with contrast under both ultrasound (US) and X-ray imaging. The radiodensity properties of varying formulations of soft PVC-based gels were characterized to allow adjustable image intensity and contrast. Using this data, a phantom creation workflow was established which can be easily adapted to match radiodensity values of other organs and soft tissues in the body. Internal kidney structures such as the medulla and ureter were created using a two-part molding process to allow greater phantom customization. The kidney phantoms were imaged under US and X-ray scanners to compare the contrast enhancement of a PVC-based medulla versus a silicone-based medulla. Silicone was found to have higher attenuation than plastic under X-ray imaging, but poor quality under US imaging. PVC was found to exhibit good contrast under X-ray imaging and excellent performance for US imaging. Finally, the durability and shelf life of our PVC-based phantoms were observed to be vastly superior to that of common agar-based phantoms. The work presented here allows extended periods of usage and storage for each kidney phantom while simultaneously preserving anatomical detail, contrast under dual-modality imaging, and low cost of materials.
PubMed: 36793656
DOI: 10.1117/12.2611592 -
Contributions To Nephrology 2021Clinical Background: Renal involvement in sickle cell disease (SCD), called sickle cell nephropathy (SCN), includes several renal manifestations, such as renal... (Review)
Review
Clinical Background: Renal involvement in sickle cell disease (SCD), called sickle cell nephropathy (SCN), includes several renal manifestations, such as renal acidification defect, distal nephron dysfunction, renal papillary necrosis, and proteinuria related to glomerular injury, leading to end-stage renal disease. Epidemiology: Many patients with SCD have a defect in urinary concentration, a problem caused by the destruction of the renal medulla that initiates in childhood. The presence of proteinuria in SCD is age-related and starts as microalbuminuria in adolescence and progresses to macroalbuminuria. Proteinuria is responsible for the progression to chronic kidney disease in some patients with SCD with glomerular filtration rate (GFR) decreased due to interactions between various processes involving the vascular, glomerular, tubular, and interstitial compartments of the kidney. Challenges: Renal complications are hardly identifiable in the early stages, as serum creatinine increases only in the final stages of SCN. Subnormal GFR and elevated serum creatinine levels develop only when there is significant proteinuria. Prevention and Treatment: The identification of biomarkers of early, non-invasive kidney injury, and their inclusion in clinical practice will contribute to the identification of the mechanisms involved in the development of renal syndromes, facilitating the development of more effective strategies in the prevention and treatment of SCD.
Topics: Adolescent; Anemia, Sickle Cell; Biomarkers; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Renal Insufficiency, Chronic
PubMed: 34343995
DOI: 10.1159/000517703 -
Neuroscience Bulletin Jun 2024The kidneys are essential organs that help maintain homeostasis, and their function is regulated by the neural system. Despite the anatomical multi-synaptic connection...
The kidneys are essential organs that help maintain homeostasis, and their function is regulated by the neural system. Despite the anatomical multi-synaptic connection between the central autonomic nuclei and the kidneys, it remains unclear whether there are any variations in neural connections between the nervous systems and the renal cortex and medulla in male and female mice. Here, we used the pseudorabies virus to map the central innervation network of the renal cortex and medulla in both sexes. The data revealed that specific brain regions displayed either a contralateral-bias or ipsilateral-bias pattern while kidney-innervating neurons distributed symmetrically in the midbrain and hindbrain. Sex differences were observed in the distribution of neurons connected to the left kidney, as well as those connected to the renal cortex and medulla. Our findings provide a comprehensive understanding of the brain-kidney network in both males and females and may help shed light on gender differences in kidney function and disease susceptibility in humans.
PubMed: 38896358
DOI: 10.1007/s12264-024-01240-z -
BMC Nephrology Apr 2022Renal perfusion may redistribute from cortex to medulla during systemic hypovolaemia and after renal ischaemia for other reasons, but there is no consensus on this...
BACKGROUND
Renal perfusion may redistribute from cortex to medulla during systemic hypovolaemia and after renal ischaemia for other reasons, but there is no consensus on this matter. We studied renal perfusion after renal ischaemia and reperfusion.
METHODS
Renal perfusion distribution was examined by use of Gadolinium-labeled microspheres (MS) after 2 h (hrs) and 4 h ischaemia of the pig kidney followed by 4 h of reperfusion. Intra-arterial injected MS are trapped in the glomeruli in renal cortex, which means that MS are not present in the medulla under normal physiological conditions.
RESULTS
Visual evaluation after reperfusion demonstrated that MS redistributed from the renal cortex to the medulla in 6 out of 16 pigs (38%) subjected to 4 h ischaemia and in one out of 18 pigs subjected to 2 h ischaemia. Central renal uptake of MS covering the medullary/total renal uptake was significantly higher in kidneys subjected to 4 h ischaemia compared with pigs subjected to 2 h ischaemia (69 ± 5% vs. 63 ± 1%, p < 0.001), and also significantly higher than in the contralateral kidney (69 ± 5% vs. 63 ± 2%, p < 0.001). Analysis of blood and urine demonstrated no presence of radioactivity.
CONCLUSION
The study demonstrated the presence of MS in the renal medulla in response to renal ischaemia and reperfusion suggesting that severe ischaemia and reperfusion of the pig kidney leads to opening of functional shunts bypassing glomeruli.
Topics: Animals; Humans; Ischemia; Kidney; Kidney Medulla; Reperfusion; Reperfusion Injury; Swine
PubMed: 35428270
DOI: 10.1186/s12882-022-02780-0 -
American Journal of Physiology. Cell... Sep 2021The fluid in the 14 distinct segments of the renal tubule undergoes sequential transport processes that gradually convert the glomerular filtrate into the final urine.... (Review)
Review
The fluid in the 14 distinct segments of the renal tubule undergoes sequential transport processes that gradually convert the glomerular filtrate into the final urine. The solute carrier (SLC) family of proteins is responsible for much of the transport of ions and organic molecules along the renal tubule. In addition, some SLC family proteins mediate housekeeping functions by transporting substrates for metabolism. Here, we have developed a curated list of SLC family proteins. We used the list to produce resource webpages that map these proteins and their transcripts to specific segments along the renal tubule. The data were used to highlight some interesting features of expression along the renal tubule including sex-specific expression in the proximal tubule and the role of accessory proteins (β-subunit proteins) that are thought to be important for polarized targeting in renal tubule epithelia. Also, as an example of application of the data resource, we describe the patterns of acid-base transporter expression along the renal tubule.
Topics: Animals; Biological Transport; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Glomerulus; Kidney Medulla; Kidney Tubules; Male; Mice; Molecular Sequence Annotation; Organoids; Sex Factors; Single-Cell Analysis; Solute Carrier Proteins
PubMed: 34191628
DOI: 10.1152/ajpcell.00197.2021