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Annual Review of Physiology Feb 2021SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from... (Review)
Review
SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose-dependent and -independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone.
Topics: Animals; Cardiovascular System; Humans; Kidney Glomerulus; Kidney Tubules, Proximal; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 33197224
DOI: 10.1146/annurev-physiol-031620-095920 -
Clinical Journal of the American... Aug 2014The glomerulus, the filtering unit of the kidney, is a unique bundle of capillaries lined by delicate fenestrated endothelia, a complex mesh of proteins that serve as... (Review)
Review
The glomerulus, the filtering unit of the kidney, is a unique bundle of capillaries lined by delicate fenestrated endothelia, a complex mesh of proteins that serve as the glomerular basement membrane and specialized visceral epithelial cells that form the slit diaphragms between interdigitating foot processes. Taken together, this arrangement allows continuous filtration of the plasma volume. The dynamic physical forces that determine the single nephron glomerular filtration are considered. In addition, new insights into the cellular and molecular components of the glomerular tuft and their contribution to glomerular disorders are explored.
Topics: Animals; Capillary Permeability; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney Diseases; Kidney Glomerulus; Models, Biological
PubMed: 24875196
DOI: 10.2215/CJN.09400913 -
Nature Reviews. Nephrology Jun 2020Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney... (Review)
Review
Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium-glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium-glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.
Topics: Cellular Senescence; Chlorides; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fibrosis; Glomerular Filtration Barrier; Glomerular Filtration Rate; Glucose; Humans; Hypertrophy; Inflammation; Kidney Glomerulus; Kidney Tubules; Nephrons; Nitric Oxide; Renal Reabsorption; Sodium; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 32152499
DOI: 10.1038/s41581-020-0256-y -
Cell Proliferation Mar 2020In recent years, although the development of clinical therapy for diabetic kidney disease (DKD) has made great progress, the progression of DKD still cannot be... (Review)
Review
In recent years, although the development of clinical therapy for diabetic kidney disease (DKD) has made great progress, the progression of DKD still cannot be controlled. Therefore, further study of the pathogenesis of DKD and improvements in DKD treatment are crucial for prognosis. Traditional studies have shown that podocyte injury plays an important role in this process. Recently, it has been found that glomerulotubular balance and tubuloglomerular feedback (TGF) may be involved in the progression of DKD. Glomerulotubular balance is the specific gravity absorption of the glomerular ultrafiltrate by the proximal tubules, which absorbs only 65% to 70% of the ultrafiltrate. This ensures that the urine volume will not change much regardless of whether the glomerular filtration rate (GFR) increases or decreases. TGF is one of the significant mechanisms of renal blood flow and self-regulation of GFR, but how they participate in the development of DKD in the pathological state and the specific mechanism is not clear. Injury to tubular epithelial cells (TECs) is the key link in DKD. Additionally, injury to glomerular endothelial cells (GECs) plays a key role in the early occurrence and development of DKD. However, TECs and GECs are close to each other in anatomical position and can crosstalk with each other, which may affect the development of DKD. Therefore, the purpose of this review was to summarize the current knowledge on the crosstalk between TECs and GECs in the pathogenesis of DKD and to highlight specific clinical and potential therapeutic strategies.
Topics: Animals; Diabetic Nephropathies; Disease Progression; Endothelium; Humans; Kidney Glomerulus; Kidney Tubules; Urothelium
PubMed: 31925859
DOI: 10.1111/cpr.12763 -
Nephrologie & Therapeutique Apr 2016This article summarizes the past, present, and future promise of multiphoton excitation fluorescence microscopy for intravital kidney imaging. During the past 15years,... (Review)
Review
This article summarizes the past, present, and future promise of multiphoton excitation fluorescence microscopy for intravital kidney imaging. During the past 15years, several high-power visual research approaches have been developed using multiphoton imaging to study the normal functions of the healthy, intact, living kidney, and the various molecular and cellular mechanisms of the development of kidney diseases. In this review, the main focus will be on intravital multiphoton imaging of the glomerulus, the structure and function of the glomerular filtration barrier, especially the podocyte. Examples will be given for the combination of two powerful research tools, in vivo multiphoton imaging and mouse genetics using commercially available whole animal models for the detailed characterization of glomerular cell types, their function and fate, and for the better understanding of the molecular mechanisms of glomerular pathologies. One of the new modalities of multiphoton imaging, serial imaging of the same glomerulus in the same animal over several days will be emphasized for its potential for further advancing the field of nephrology research.
Topics: Animals; Humans; Intravital Microscopy; Kidney; Kidney Diseases; Kidney Glomerulus; Mice; Microscopy, Fluorescence, Multiphoton; Podocytes; Predictive Value of Tests; Reproducibility of Results; Sensitivity and Specificity
PubMed: 26968479
DOI: 10.1016/j.nephro.2016.01.004 -
Diabetologia Aug 2016Diabetic nephropathy is the main cause of end-stage renal failure in the Western world. In diabetes, metabolic and haemodynamic perturbations disrupt the integrity of... (Review)
Review
Diabetic nephropathy is the main cause of end-stage renal failure in the Western world. In diabetes, metabolic and haemodynamic perturbations disrupt the integrity of the glomerular filtration barrier, leading to ultrastructural alterations of the glomeruli, including podocyte foot process fusion and detachment, glomerular basement membrane thickening, reduced endothelial cell glycocalyx, and mesangial extracellular matrix accumulation and glomerulosclerosis, ultimately leading to albuminuria and end-stage renal disease. Many vascular growth factors, such as angiopoietins, are implicated in glomerular biology. In normal physiology angiopoietins regulate the function of the glomerular filtration barrier. When they are dysregulated, however, as they are in diabetes, they drive the cellular mechanisms that mediate diabetic glomerular pathology. Modulation of angiopoietins expression and signalling has been proposed as a tool to correct the cellular mechanisms involved in the pathophysiology of diabetic microvascular disease, such as retinopathy in humans. Future work might evaluate whether this novel therapeutic approach should be extended to diabetic kidney disease.
Topics: Albuminuria; Angiopoietins; Animals; Diabetic Nephropathies; Endothelial Cells; Humans; Kidney Glomerulus
PubMed: 27207083
DOI: 10.1007/s00125-016-3995-3 -
Clinical Journal of the American... Jun 2019
Topics: Diabetes Mellitus, Type 1; Humans; Kidney; Kidney Diseases; Kidney Glomerulus
PubMed: 31175079
DOI: 10.2215/CJN.05330419 -
Annual Review of Physiology 2016The glomerulus is a highly specialized microvascular bed that filters blood to form primary urinary filtrate. It contains four cell types: fenestrated endothelial cells,... (Review)
Review
The glomerulus is a highly specialized microvascular bed that filters blood to form primary urinary filtrate. It contains four cell types: fenestrated endothelial cells, specialized vascular support cells termed podocytes, perivascular mesangial cells, and parietal epithelial cells. Glomerular cell-cell communication is critical for the development and maintenance of the glomerular filtration barrier. VEGF, ANGPT, EGF, SEMA3A, TGF-β, and CXCL12 signal in paracrine fashions between the podocytes, endothelium, and mesangium associated with the glomerular capillary bed to maintain filtration barrier function. In this review, we summarize the current understanding of these signaling pathways in the development and maintenance of the glomerulus and the progression of disease.
Topics: Animals; Capillaries; Endothelial Cells; Endothelium, Vascular; Humans; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Kidney Glomerulus; Signal Transduction
PubMed: 26863327
DOI: 10.1146/annurev-physiol-021115-105412 -
JCI Insight Jan 2022Alport syndrome (AS) is a genetic disorder caused by mutations in type IV collagen that lead to defective glomerular basement membrane, glomerular filtration barrier...
Alport syndrome (AS) is a genetic disorder caused by mutations in type IV collagen that lead to defective glomerular basement membrane, glomerular filtration barrier (GFB) damage, and progressive chronic kidney disease. While the genetic basis of AS is well known, the molecular and cellular mechanistic details of disease pathogenesis have been elusive, hindering the development of mechanism-based therapies. Here, we performed intravital multiphoton imaging of the local kidney tissue microenvironment in a X-linked AS mouse model to directly visualize the major drivers of AS pathology. Severely distended glomerular capillaries and aneurysms were found accompanied by numerous microthrombi, increased glomerular endothelial surface layer (glycocalyx) and immune cell homing, GFB albumin leakage, glomerulosclerosis, and interstitial fibrosis by 5 months of age, with an intermediate phenotype at 2 months. Renal histology in mouse or patient tissues largely failed to detect capillary aberrations. Treatment of AS mice with hyaluronidase or the ACE inhibitor enalapril reduced the excess glomerular endothelial glycocalyx and blocked immune cell homing and GFB albumin leakage. This study identified central roles of glomerular mechanical forces and endothelial and immune cell activation early in AS, which could be therapeutically targeted to reduce mechanical strain and local tissue inflammation and improve kidney function.
Topics: Animals; Capillaries; Cellular Microenvironment; Disease Models, Animal; Humans; Intravital Microscopy; Kidney Glomerulus; Male; Mice; Nephritis, Hereditary
PubMed: 34793332
DOI: 10.1172/jci.insight.152676 -
Experimental Cell Research May 2012The kidney's glomerular filtration barrier consists of two cells-podocytes and endothelial cells-and the glomerular basement membrane (GBM), a specialized extracellular... (Review)
Review
The kidney's glomerular filtration barrier consists of two cells-podocytes and endothelial cells-and the glomerular basement membrane (GBM), a specialized extracellular matrix that lies between them. Like all basement membranes, the GBM consists mainly of laminin, type IV collagen, nidogen, and heparan sulfate proteoglycan. However, the GBM is unusually thick and contains particular members of these general protein families, including laminin-521, collagen α3α4α5(IV), and agrin. Knockout studies in mice and genetic findings in humans show that the laminin and type IV collagen components are particularly important for GBM structure and function, as laminin or collagen IV gene mutations cause filtration defects and renal disease of varying severities, depending on the nature of the mutations. These studies suggest that the GBM plays a crucial role in establishing and maintaining the glomerular filtration barrier.
Topics: Animals; Collagen Type IV; Glomerular Basement Membrane; Glomerular Filtration Barrier; Humans; Kidney Glomerulus; Laminin; Membrane Glycoproteins; Mice; Models, Biological
PubMed: 22410250
DOI: 10.1016/j.yexcr.2012.02.031