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Frontiers in Cell and Developmental... 2023Protein reabsorption in renal proximal tubules is essential for maintaining nutrient homeostasis. Renal proximal tubule-specific gene knockout is a powerful method to...
Protein reabsorption in renal proximal tubules is essential for maintaining nutrient homeostasis. Renal proximal tubule-specific gene knockout is a powerful method to assess the function of genes involved in renal proximal tubule protein reabsorption. However, the lack of inducible renal proximal tubule-specific Cre recombinase-expressing mouse strains hinders the study of gene function in renal proximal tubules. To facilitate the functional study of genes in renal proximal tubules, we developed an knock-in mouse strain expressing a Cre recombinase-estrogen receptor fusion protein under the control of the promoter of the gene, a protein reabsorption receptor in renal proximal tubules. knock-in mice were generated using the CRISPR/Cas9 strategy, and the tissue specificity of Cre activity was investigated using the Cre/loxP reporter system. We showed that the expression pattern of CreERT2-mEGFP in mice was consistent with that of the endogenous gene. Furthermore, we showed that the Cre activity in knock-in mice was only detected in renal proximal tubules with high tamoxifen induction efficiency. As a proof-of-principle study, we demonstrated that renal proximal tubule-specific knockout of using AMN led to albumin accumulation in renal proximal tubular epithelial cells. The mouse is a powerful tool for conditional gene knockout in renal proximal tubules and should offer useful insight into the physiological function of genes expressed in renal proximal tubules.
PubMed: 37215091
DOI: 10.3389/fcell.2023.1171637 -
Clinical Kidney Journal Oct 2023In chronic kidney disease (CKD) patients, hypofiltration may lead to the accumulation of drugs that are cleared mainly by the kidney and, vice versa, hyperfiltration may... (Review)
Review
In chronic kidney disease (CKD) patients, hypofiltration may lead to the accumulation of drugs that are cleared mainly by the kidney and, vice versa, hyperfiltration may cause augmented renal excretion of the same drugs. In this review we mainly focus on the issue of whether hyperfiltration significantly impacts the renal clearance of drugs and whether the same alteration may demand an up-titration of the doses applied in clinical practice. About half of severely ill, septic patients and patients with burns show glomerular hyperfiltration and this may lead to enhanced removal of drugs such as hydrophilic antibiotics and a higher risk of antibiotic treatment failure. In general, hyperfiltering obese individuals show higher absolute drug clearances than non-obese control subjects, but this depends on the body size descriptor adopted to adjust for fat excess. Several mechanisms influence pharmacokinetics in type 2 diabetes, including renal hyperfiltration, reduced tubular reabsorption and augmented tubular excretion. However, no consistent pharmacokinetic alteration has been identified in hyperfiltering obese subjects and type 2 diabetics. Non-vitamin K antagonist oral anticoagulants (NOACs) have exhibited lower plasma concentrations in hyperfiltering patients in some studies in patients with atrial fibrillation, but a recent systematic review failed to document any excess risk for stroke and systemic embolism in these patients. Hyperfiltration is common among severely ill patients in intensive care units and drug levels should be measured whenever possible in these high-risk patients to prevent underdosing and treatment failure. Hyperfiltration is also common in patients with obesity or type 2 diabetes, but no consistent pharmacokinetic alteration has been described in these patients. No NOAC dose adjustment is indicated in patients with atrial fibrillation being treated with these drugs.
PubMed: 37779850
DOI: 10.1093/ckj/sfad079 -
BMC Medicine Apr 2022Reliable assessment of glycemia is central to the management of diabetes. The kidneys play a vital role in maintaining glucose homeostasis through glucose filtration,... (Review)
Review
Reliable assessment of glycemia is central to the management of diabetes. The kidneys play a vital role in maintaining glucose homeostasis through glucose filtration, reabsorption, consumption, and generation. This review article highlights the role of the kidneys in glucose metabolism and discusses the benefits, pitfalls, and evidence behind the glycemic markers in patients with chronic kidney disease. We specifically highlight the role of continuous glucose monitoring as an emerging minimally invasive technique for glycemic assessment.
Topics: Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Glucose; Glycated Hemoglobin; Humans; Renal Insufficiency, Chronic
PubMed: 35414081
DOI: 10.1186/s12916-022-02316-1 -
Cells Jul 2020The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The... (Review)
Review
The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The extracellular calcium-sensing receptor (CaSR) elicits a number of adaptive reactions to increased plasma Ca levels including the control of parathyroid hormone release and regulation of the renal calcium handling. Calcium reabsorption in the distal nephron of the kidney is functionally coupled to sodium transport. Apart from Ca transport systems, CaSR signaling affects relevant distal Na-(K)-2Cl cotransporters, NKCC2 and NCC. NKCC2 and NCC are activated by a kinase cascade comprising with-no-lysine [K] kinases (WNKs) and two homologous Ste20-related kinases, SPAK and OSR1. Gain-of-function mutations within the WNK-SPAK/OSR1-NKCC2/NCC pathway lead to renal salt retention and hypertension, whereas loss-of-function mutations have been associated with salt-losing tubulopathies such as Bartter or Gitelman syndromes. A Bartter-like syndrome has been also described in patients carrying gain-of-function mutations in the CaSR gene. Recent work suggested that CaSR signals via the WNK-SPAK/OSR1 cascade to modulate salt reabsorption along the distal nephron. The review presented here summarizes the latest progress in understanding of functional interactions between CaSR and WNKs and their potential impact on the renal salt handling and blood pressure.
Topics: Animals; Humans; Kidney; Nephrons; Protein Serine-Threonine Kinases; Receptors, Calcium-Sensing; Signal Transduction
PubMed: 32659887
DOI: 10.3390/cells9071644 -
Frontiers in Bioscience (Landmark... Mar 2023Maintaining a balance between the supply and demand of oxygen is vital for proper organ function. Most types of acute kidney injury (AKI) are characterized by hypoxia, a... (Review)
Review
Maintaining a balance between the supply and demand of oxygen is vital for proper organ function. Most types of acute kidney injury (AKI) are characterized by hypoxia, a state where the supply of oxygen cannot match the demand for normal cellular activities. Hypoxia results from hypo perfusion and impaired microcirculation in the kidney. It inhibits mitochondrial oxidative phosphorylation, resulting in a decrease in production of adenosine triphosphate (ATP), which is essential to power tubular transport activities, especially reabsorption of Na+, and other vital cellular activities. To ameliorate AKI, the majority of studies have focused on increasing renal oxygen delivery by restoring renal blood flow and altering intra-renal hemodynamics. However, to date these approaches remain inadequate. In addition to augmenting oxygen supply, increasing renal blood flow also increases glomerular filtration rate, leading to increased solute deliver and workload for the renal tubules, causing an increase in oxygen consumption. The relationship between Na+ reabsorption and oxygen expenditure in the kidney is linear. Experimental models have demonstrated that inhibition of Na+ reabsorption can alleviate AKI. Since the proximal tubules reabsorb approximately 65% of filtered Na+, consuming the largest portion of oxygen, many studies focus on examining the effects of inhibiting Na+ reabsorption in this segment. Potential therapeutics that have been examined include acetazolamide, dopamine and its analog, inhibitors of the renin-angiotensin II system, atrial natriuretic peptide, and empagliflozin. The effectiveness of inhibition of Na+ reabsorption in the thick ascending limb of the Loop of Henle by furosemide has been also examined. While these approaches produced impressive results in animal models, their clinical benefits remain mixed. This review summarizes the progress in this area and argues that the combination of increasing oxygen supply with decreasing oxygen consumption or different approaches to reducing oxygen demand will be more efficacious.
Topics: Animals; Kidney; Acute Kidney Injury; Kidney Tubules, Proximal; Sodium; Oxygen; Hypoxia; Oxygen Consumption
PubMed: 37005768
DOI: 10.31083/j.fbl2803062 -
International Journal of Molecular... Oct 2022In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na and water reabsorption in... (Review)
Review
In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na and water reabsorption in the proximal tubule, and the tubuloglomerular feedback which senses the Na concentration in the filtrate by the juxtaglomerular apparatus to provide negative feedback on the glomerular filtration rate. In essence, the two mechanisms regulate renal oxygen consumption. The renal hyperfiltration driven by increased glomerular filtration pressure and by glucose diuresis can affect renal O consumption that unleashes detrimental sympathetic activation. The sodium-glucose co-transporters inhibitors (SGLTi) can rebalance the reabsorption of Na coupled with glucose and can restore renal O demand, diminishing neuroendocrine activation. Large randomized controlled studies performed in diabetic subjects, in heart failure, and in populations with chronic kidney disease with and without diabetes, concordantly address effective action on heart failure exacerbations and renal adverse outcomes.
Topics: Diabetes Mellitus; Diabetic Nephropathies; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 36233288
DOI: 10.3390/ijms231911987 -
American Journal of Nephrology 2022In metabolic acidosis, a negative calcium balance is induced by decreased renal tubular calcium reabsorption. This occurs independently of the action of parathyroid... (Review)
Review
BACKGROUND
In metabolic acidosis, a negative calcium balance is induced by decreased renal tubular calcium reabsorption. This occurs independently of the action of parathyroid hormone or vitamin D and was attributed to a direct action of metabolic acidosis on the renal tubular cells. The latter has been verified by recent studies on the molecular levels in the kidney.
SUMMARY
Whereas the regulatory role of urinary calcium excretion was traditionally assigned to the transcellular calcium transport in the distal convoluted tubule (DCT) and connecting tubule (CNT), most of the calcium reabsorption from the glomerular filtrate paracellularly occurs through the tight junctions in the proximal tubule (PT) and the thick ascending limb (TAL) of Henle's loop. Interestingly, all these nephron segments participate in producing hypercalciuria caused by metabolic acidosis. Claudin-2 is the major route of paracellular calcium transport in the PT and was downregulated in rats with 5 days' NH4Cl loading. In the TAL, the lumen-positive voltage produced by apical K+ recycling drives paracellular reabsorption of Ca2+ and Mg2+ via the claudin-16/19 complex. Activation of calcium-sensing receptor (CaSR) by extracellular calcium upregulates claudin-14, which in turn interacts with the claudin-16/19 complex and inhibits its cation permeability. This TAL CaSR-claudins axis was activated by chronic NH4Cl loading in rats. Finally, the major transcellular calcium transporters TRPV5 and 28K calcium-binding protein in the DCT-CNT were also downregulated by NH4Cl or acetazolamide administration in mice.
KEY MESSAGES
Both paracellular and transcellular calcium transport pathways in the kidney are regulated by metabolic acidosis and lead to renal calcium wasting. In the PT, claudin-2 is downregulated by acidic pH. In the TAL of Henle's loop, CaSR is stimulated by the ionized calcium released from bone and upregulates claudin-14, which in turn inhibits the claudin-16/19 complex and leads to calcium and magnesium wasting. Finally, the transcellular calcium transporters, TRPV5 and calbindin-D28K, are downregulated by metabolic acidosis in the DCT and CNT.
Topics: Mice; Rats; Animals; Calcium; Hypercalciuria; Claudin-2; Claudins; Kidney; Acidosis
PubMed: 36450225
DOI: 10.1159/000528089 -
Frontiers in Medicine 2021Diabetic nephropathy is the most common cause of end-stage renal disease worldwide. Control of blood glucose and blood pressure (BP) reduces the risk of developing this... (Review)
Review
Diabetic nephropathy is the most common cause of end-stage renal disease worldwide. Control of blood glucose and blood pressure (BP) reduces the risk of developing this complication, but once diabetic nephropathy is established, it is then only possible to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a novel class of oral hypoglycemic agents that increase urinary glucose excretion by suppressing glucose reabsorption at the renal proximal tubule. SGLT2is lower glycated hemoglobin (HbA1c) without increasing the risk of hypoglycemia, induce weight loss and improve various metabolic parameters including BP, lipid profile, albuminuria and uric acid. Several clinical trials have shown that SGLT2is (empagliflozin, dapagliflozin canagliflozin, and ertugliflozin) improve cardiovascular and renal outcomes and mortality in patients with type 2 diabetes. Effects of SGLT2is on the kidney can be explained by multiple pathways. SGLT2is may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT2is are associated with a reduction in glomerular hyperfiltration, an effect which is mediated by the increase in natriuresis, the re-activation of tubule-glomerular feedback and independent of glycemic control. In this review, we will focus on renal results of major cardiovascular and renal outcome trials and we will describe direct and indirect mechanisms through which SGLT2is confer renal protection.
PubMed: 34150796
DOI: 10.3389/fmed.2021.654557 -
Electrolyte & Blood Pressure : E & BP Jun 2021Urate is produced in the liver by the degradation of purines from the diet and nucleotide turnover and excreted by the kidney and gut. The kidney is the major route of... (Review)
Review
Urate is produced in the liver by the degradation of purines from the diet and nucleotide turnover and excreted by the kidney and gut. The kidney is the major route of urate removal and has a pivotal role in the regulation of urate homeostasis. Approximately 10% of the glomerular filtered urate is excreted in the urine, and the remainder is reabsorbed by the proximal tubule. However, the transport of urate in the proximal tubule is bidirectional: reabsorption and secretion. Thus, an increase in reabsorption or a decrease in secretion may induce hyperuricemia. In contrast, a decrease in reabsorption or an increase in secretion may result in hyperuricosuria. In the proximal tubule, urate reabsorption is mainly mediated by apical URAT1 () and basolateral GLUT9 () transporter. OAT4 () also acts in urate reabsorption in the apical membrane, and its polymorphism is associated with the risk of hyperuricemia. Renal hypouricemia is caused by or loss-of-function mutations, and it may be complicated by exercise-induced acute kidney injury. URAT1 and GLUT9 are also drug targets for uricosuric agents. Sodium-glucose cotransporter inhibitors may induce hyperuricosuria by inhibiting GLUT9b located in the apical plasma membrane. Urate secretion is mediated by basolateral OAT1 () and OAT3 () and apical ATP-binding cassette super-family G member 2 (), NPT1 (), and NPT4 () transporter in the proximal tubule. NPT1 and NPT4 may be key players in renal urate secretion in humans, and deletion of and in mice leads to decreased urate excretion. Dysfunctional variants of inhibit urate secretion from the gut and kidney and may cause gout. In summary, the net result of urate transport in the proximal tubule is determined by the dominance of transporters between reabsorption (URAT1, OAT4, and GLUT9) and secretion (ABCG2, NPT1, NPT4, OAT1, and OAT3).
PubMed: 34290818
DOI: 10.5049/EBP.2021.19.1.1