111 results on '"Scott C. Thomson"'
Search Results
2. A role for tubular Na+/H+exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin
- Author
-
Akira Onishi, Maria Crespo-Masip, Kumar Sharma, Scott C. Thomson, Volker Vallon, Yiling Fu, Rohit Patel, Manoocher Soleimani, Manjula Darshi, Panai Song, Winnie Huang, Young Chul Kim, and Brent Freeman
- Subjects
medicine.medical_specialty ,urogenital system ,Physiology ,Chemistry ,Reabsorption ,Bicarbonate ,Kidney metabolism ,Natriuresis ,Sodium–hydrogen antiporter ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Renin–angiotensin system ,medicine ,Empagliflozin ,SGLT2 Inhibitor - Abstract
Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this “potential bicarbonate.” The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.
- Published
- 2020
3. The tubular hypothesis of nephron filtration and diabetic kidney disease
- Author
-
Volker Vallon and Scott C. Thomson
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Kidney Glomerulus ,030232 urology & nephrology ,Renal function ,Nephron ,Nitric Oxide ,Article ,03 medical and health sciences ,Sodium-Glucose Transporter 1 ,0302 clinical medicine ,Chlorides ,Sodium-Glucose Transporter 2 ,Glomerular Filtration Barrier ,Internal medicine ,Diabetes Mellitus ,medicine ,Humans ,Diabetic Nephropathies ,Sodium-Glucose Transporter 2 Inhibitors ,Cellular Senescence ,Tubuloglomerular feedback ,Inflammation ,urogenital system ,business.industry ,Reabsorption ,Sodium ,Renal Reabsorption ,Hypertrophy ,Nephrons ,Fibrosis ,Glucose ,Kidney Tubules ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Diabetes Mellitus, Type 2 ,Nephrology ,Macula densa ,business ,Glomerular hyperfiltration ,Glomerular Filtration Rate - Abstract
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.
- Published
- 2020
4. Effect of renal tubule-specific knockdown of the Na+/H+exchanger NHE3 in Akita diabetic mice
- Author
-
Maria Crespo-Masip, Manoocher Soleimani, Kumar Sharma, Winnie Huang, Josselin Nespoux, Panai Song, Brent Freeman, Akira Onishi, Manjula Darshi, Yiling Fu, Volker Vallon, Young Chul Kim, Rohit Patel, and Scott C. Thomson
- Subjects
Gene isoform ,medicine.medical_specialty ,Gene knockdown ,urogenital system ,Physiology ,medicine.disease ,Diabetic nephropathy ,Sodium–hydrogen antiporter ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Diabetes mellitus ,Internal medicine ,medicine ,Albuminuria ,Secretion ,Ammonium ,medicine.symptom - Abstract
Na+/H+exchanger isoform 3 (NHE3) contributes to Na+/bicarbonate reabsorption and ammonium secretion in early proximal tubules. To determine its role in the diabetic kidney, type 1 diabetic Akita mice with tubular NHE3 knockdown [Pax8-Cre; NHE3-knockout (KO) mice] were generated. NHE3-KO mice had higher urine pH, more bicarbonaturia, and compensating increases in renal mRNA expression for genes associated with generation of ammonium, bicarbonate, and glucose (phosphoenolpyruvate carboxykinase) in proximal tubules and H+and ammonia secretion and glycolysis in distal tubules. This left blood pH and bicarbonate unaffected in nondiabetic and diabetic NHE3-KO versus wild-type mice but was associated with renal upregulation of proinflammatory markers. Higher renal phosphoenolpyruvate carboxykinase expression in NHE3-KO mice was associated with lower Na+-glucose cotransporter (SGLT)2 and higher SGLT1 expression, indicating a downward tubular shift in Na+and glucose reabsorption. NHE3-KO was associated with lesser kidney weight and glomerular filtration rate (GFR) independent of diabetes and prevented diabetes-associated albuminuria. NHE3-KO, however, did not attenuate hyperglycemia or prevent diabetes from increasing kidney weight and GFR. Higher renal gluconeogenesis may explain similar hyperglycemia despite lower SGLT2 expression and higher glucosuria in diabetic NHE3-KO versus wild-type mice; stronger SGLT1 engagement could have affected kidney weight and GFR responses. Chronic kidney disease in humans is associated with reduced urinary excretion of metabolites of branched-chain amino acids and the tricarboxylic acid cycle, a pattern mimicked in diabetic wild-type mice. This pattern was reversed in nondiabetic NHE3-KO mice, possibly reflecting branched-chain amino acids use for ammoniagenesis and tricarboxylic acid cycle upregulation to support formation of ammonia, bicarbonate, and glucose in proximal tubule. NHE3-KO, however, did not prevent the diabetes-induced urinary downregulation in these metabolites.
- Published
- 2019
5. Knockout of Na+-glucose cotransporter SGLT1 mitigates diabetes-induced upregulation of nitric oxide synthase NOS1 in the macula densa and glomerular hyperfiltration
- Author
-
Yiling Fu, Panai Song, Ruisheng Liu, Scott C. Thomson, Charlotte van Ginkel, Rohit Patel, Winnie Huang, Akira Onishi, Young Chul Kim, Volker Vallon, Brent Freeman, and Hermann Koepsell
- Subjects
Blood Glucose ,medicine.medical_specialty ,Physiology ,NOS1 ,Blood Pressure ,Nitric Oxide Synthase Type I ,Kidney ,Diabetes Mellitus, Experimental ,Sodium-Glucose Transporter 1 ,Sodium-Glucose Transporter 2 ,Downregulation and upregulation ,Internal medicine ,Diabetes mellitus ,Renin ,medicine ,Albuminuria ,Animals ,Diabetic Nephropathies ,Sodium-Glucose Transporter 2 Inhibitors ,Mice, Knockout ,biology ,Chemistry ,digestive, oral, and skin physiology ,medicine.disease ,Renal Reabsorption ,Up-Regulation ,Renal glucose reabsorption ,Mice, Inbred C57BL ,Nitric oxide synthase ,Diabetes Mellitus, Type 1 ,Endocrinology ,medicine.anatomical_structure ,Mice, Inbred DBA ,biology.protein ,Macula densa ,Cotransporter ,Biomarkers ,Glomerular hyperfiltration ,Research Article ,Glomerular Filtration Rate ,Signal Transduction - Abstract
Na+-glucose cotransporter (SGLT)1 mediates glucose reabsorption in late proximal tubules. SGLT1 also mediates macula densa (MD) sensing of an increase in luminal glucose, which increases nitric oxide (NO) synthase 1 (MD-NOS1)-mediated NO formation and potentially glomerular filtratrion rate (GFR). Here, the contribution of SGLT1 was tested by gene knockout (−/−) in type 1 diabetic Akita mice. A low-glucose diet was used to prevent intestinal malabsorption in Sglt1−/−mice and minimize the contribution of intestinal SGLT1. Hyperglycemia was modestly reduced in Sglt1−/−versus littermate wild-type Akita mice (480 vs. 550 mg/dl), associated with reduced diabetes-induced increases in GFR, kidney weight, glomerular size, and albuminuria. Blunted hyperfiltration was confirmed in streptozotocin-induced diabetic Sglt1−/−mice, associated with similar hyperglycemia versus wild-type mice (350 vs. 385 mg/dl). Absence of SGLT1 attenuated upregulation of MD-NOS1 protein expression in diabetic Akita mice and in response to SGLT2 inhibition in nondiabetic mice. During SGLT2 inhibition in Akita mice, Sglt1−/−mice had likewise reduced blood glucose (200 vs. 300 mg/dl), associated with lesser MD-NOS1 expression, GFR, kidney weight, glomerular size, and albuminuria. Absence of Sglt1 in Akita mice increased systolic blood pressure, associated with suppressed renal renin mRNA expression. This may reflect fluid retention due to blunted hyperfiltration. SGLT2 inhibition prevented the blood pressure increase in Sglt1−/−Akita mice, possibly due to additive glucosuric/diuretic effects. The data indicate that SGLT1 contributes to diabetic hyperfiltration and limits diabetic hypertension. Potential mechanisms include its role in glucose-driven upregulation of MD-NOS1 expression. This pathway may increase GFR to maintain volume balance when enhanced MD glucose delivery indicates upstream saturation of SGLTs and thus hyperreabsorption.
- Published
- 2019
6. Nitric oxide mediates anomalous tubuloglomerular feedback in rats fed high-NaCl diet after subtotal nephrectomy
- Author
-
Scott C. Thomson
- Subjects
Male ,Single nephron ,medicine.medical_specialty ,Physiology ,Kidney Glomerulus ,Subtotal nephrectomy ,Sodium Chloride ,Kidney ,Nitric Oxide ,Nephrectomy ,Nitric oxide ,Kidney Tubules, Proximal ,Judgment ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Enzyme Inhibitors ,Rats, Wistar ,Sodium Chloride, Dietary ,Diuretics ,Tubuloglomerular feedback ,Feedback, Physiological ,Chemistry ,Remnant kidney ,Sodium ,Renal Reabsorption ,Diet ,Rats ,Endocrinology ,Salt balance ,Nitric Oxide Synthase ,Glomerular Filtration Rate ,Signal Transduction ,Research Article - Abstract
Tubuloglomerular feedback (TGF) responses become anomalous in rats fed high-NaCl diet after subtotal nephrectomy (STN), such that stimulating TGF causes single nephron GFR (SNGFR) to increase rather than decrease. Micropuncture experiments were performed to determine whether this anomaly results from heightened nitric oxide response to distal delivery, which is a known mechanism for resetting TGF, or from connecting tubule TGF (cTGF), which is a novel amiloride-inhibitable system for offsetting TGF responses. Micropuncture was done in Wistar Froemter rats fed high-NaCl diet (HS) for 8–10 days after STN or sham nephrectomy. TGF was manipulated by orthograde microperfusion of Henle’s loop with artificial tubular fluid with or without NOS inhibitor, LNMMA, or the cell-impermeant amiloride analog, benzamil. SNGFR was measured by inulin clearance in tubular fluid collections from the late proximal tubule. TGF responses were quantified as the increase in SNGFR that occurred when the perfusion rate was reduced from 50 to 8 nl/min in STN or 40 to 8 nl/min in sham animals. The baseline TGF response was anomalous in STN HS (−4 ± 3 vs 14 ± 3 nl/min, P < 0.001). TGF response was normalized by perfusing STN nephron with LNMMA (14 ± 3 nl/min, P < 0.005 for ANOVA cross term) but not with benzamil (−3 ± 4 nl/min, P = 0.4 for ANOVA cross term). Anomalous TGF occurs in STN HS due to heightened effect of tubular flow on nitric oxide signaling, which increases to the point of overriding the normal TGF response. There is no role for cTGF in this phenomenon.
- Published
- 2019
7. Effects of SGLT2 inhibitor and dietary NaCl on glomerular hemodynamics assessed by micropuncture in diabetic rats
- Author
-
Volker Vallon and Scott C. Thomson
- Subjects
Male ,medicine.medical_specialty ,Physiology ,Kidney Glomerulus ,030209 endocrinology & metabolism ,Punctures ,030204 cardiovascular system & hematology ,Glomerulus (kidney) ,Streptozocin ,Diabetes Mellitus, Experimental ,Renal Circulation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Diabetic Nephropathies ,Rats, Wistar ,Sodium Chloride, Dietary ,Sodium-Glucose Transporter 2 Inhibitors ,Tubuloglomerular feedback ,Glomerular hemodynamics ,Diabetic kidney ,urogenital system ,business.industry ,Hemodynamics ,Diet, Sodium-Restricted ,Bridged Bicyclo Compounds, Heterocyclic ,Renal Reabsorption ,Blockade ,Glomerular capillary pressure ,medicine.anatomical_structure ,Endocrinology ,Editorial ,Disease Progression ,SGLT2 Inhibitor ,business ,Cotransporter ,Glomerular Filtration Rate - Abstract
It has been theorized that Na-glucose cotransporter (SGLT2) blockade slows progression of diabetic kidney disease by reducing physical strain on the glomerulus. This is the first direct measurement of intraglomerular pressure during SGLT2 blockade. Findings confirmed that SGLT2 blockade does reduce glomerular capillary pressure, that this is mediated through tubuloglomerular feedback, and that the tubuloglomerular feedback response to SGLT2 blockade involves preglomerular vasoconstriction and postglomerular vasorelaxation.
- Published
- 2021
8. 87-LB: Glycemic Variability in People with Impaired Glucose Tolerance/Prediabetes
- Author
-
Kevin Douglas, Narayan Annamalai, Scott C. Thomson, and Patrick J. Moore
- Subjects
medicine.medical_specialty ,education.field_of_study ,Erythema ,business.industry ,Endocrinology, Diabetes and Metabolism ,Population ,Type 2 diabetes ,medicine.disease ,Impaired glucose tolerance ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Prediabetes ,medicine.symptom ,Risk factor ,business ,education ,Glycemic - Abstract
The use of continuous glucose monitoring has been suggested as a method of determining glucose control in prediabetes, including understanding glucose variability, which may be a risk factor in the progression to type 2 diabetes. This pilot research study aimed to determine glycemic variability (%CV) in people diagnosed with impaired glucose tolerance (IGT)/prediabetes. The study included people aged 18 or over, with their most recent HbA1c 5.7-6.4% (39-47 mmol/mol) recorded in medical notes in the last 12 months. Pregnant patients were excluded, as were patients with diabetes. A total of 43 participants (60.5% female) from 5 primary care sites in the UK enrolled in the 2-week single arm study, wearing a FreeStyle Libre Pro Flash Glucose Monitoring SystemTM (glucose data was not available to participants). On average, HbA1c was 6.06±0.25% (42.7±2.6 mmol/mol), age was 62.5±8.3 years, BMI was 32.1±6.6 kg/m2, average time since diagnosis was 18±19 months, average Q diabetes score was 28.4±23.7% (mean±SD). Glucose variability (%CV) was 17.3±3.8%, %CV was greater during daytime hours (06:00 to 23:00) than at night (23:00 to 06:00), 17.7±4.1% and 12.9±3.5% respectively (mean±SD). %CV was greater in those with BMI180 mg/dL, 10.0 mmol/L) was 0.09±0.23 hours per day (mean±SD). Ten anticipated sensor insertion site symptoms were experienced by five participants: erythema (n=2, well-defined redness), pain (n=1), bruising (n=1), itching (n=2), rash (n=2), bleeding (n=1) and other (n=1, ‘skin irritation’), all were mild in severity and resolved. This population, with prediabetes experienced glucose variability of 17.3% (%CV). This was greater during daytime hours and in those with lower BMI ( Disclosure K. Douglas: None. N. Annamalai: None. P.J. Moore: None. S. Thomson: Research Support; Self; Abbott. Research Support; Spouse/Partner; Abbott.
- Published
- 2020
9. Renal hemodynamic effects of glucagon-like peptide-1 agonist are mediated by nitric oxide but not prostaglandin
- Author
-
Zhi Zhao Liu, Prabhleen Singh, Ali Kashkouli, and Scott C. Thomson
- Subjects
Male ,0301 basic medicine ,Agonist ,medicine.medical_specialty ,Physiology ,medicine.drug_class ,Prostaglandin ,030209 endocrinology & metabolism ,Nitric Oxide ,Renal Circulation ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Glucagon-Like Peptide 1 ,Internal medicine ,medicine ,Animals ,Renal hemodynamics ,Rats, Wistar ,Venoms ,Chemistry ,Carbohydrate ,Glucagon-like peptide-1 ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Incretin Hormone ,Prostaglandins ,Exenatide ,Peptides ,Pancreas ,Research Article - Abstract
The incretin hormone, glucagon-like peptide-1 (GLP-1), is known for responding to dietary fat and carbohydrate. It elicits effects on pancreas, gut, and brain to stabilize blood glucose levels. We have previously reported that the GLP-1 agonist, exenatide, vasodilates the kidney and suppresses proximal reabsorption. The present study was undertaken to determine whether the renal effects of exenatide are mediated by nitric oxide (NO) and/or prostaglandins. Inulin clearance (glomerular filtration rate, GFR) and urine flow rate (UV) were measured in anesthetized rats before and during exenatide infusion (1 nmol/h iv). Animals were pretreated with cyclooxygenase (COX) inhibitor (meclofenamate), NO synthase (NOS) inhibitor ( NG-monomethyl-l-arginine, l-NMMA), NO clamp (l-NMMA + sodium nitroprusside), or placebo. Effectiveness of COX inhibition was tested by measuring urinary prostaglandin E2 (UPGE2). Effectiveness of NOS blockade and NO clamp was determined by urinary NO degradation products (UNOx). Exenatide increased GFR, UV, UPGE2, and UNOx. Pretreatment with meclofenamate reduced UPGE2 by 75% and reduced the effect of exenatide on UPGE2 by 30% but did not modify the effects of exenatide on GFR or UV. Pretreatment with l-NMMA reduced UNOx and the impact of exenatide on GFR and UV by 50%. Pretreatment by NO clamp did not prevent UNOx from increasing during exenatide but blunted the effects of exenatide on GFR and UV. In conclusion, exenatide is a potent renal vasodilator and diuretic in the rat. These effects of exenatide are insensitive to COX inhibition but are mediated, in part, by NO.
- Published
- 2017
10. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition
- Author
-
Scott C. Thomson and Volker Vallon
- Subjects
medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Kidney ,Article ,03 medical and health sciences ,0302 clinical medicine ,Sodium-Glucose Transporter 2 ,Internal medicine ,Internal Medicine ,medicine ,Empagliflozin ,Humans ,Glucose homeostasis ,Sodium-Glucose Transporter 2 Inhibitors ,Tubuloglomerular feedback ,business.industry ,medicine.disease ,Renal glucose reabsorption ,Glucose ,Phlorhizin ,medicine.anatomical_structure ,Endocrinology ,Diabetes Mellitus, Type 2 ,Hyperglycemia ,Insulin Resistance ,SGLT2 Inhibitor ,business ,Glomerular hyperfiltration ,Kidney disease - Abstract
Healthy kidneys filter ∼160 g/day of glucose (∼30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ∼450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule. In the absence or with inhibition of SGLT2, the renal reabsorptive capacity for glucose declines to ∼80 g/day (the residual capacity of SGLT1), i.e. the safety valve opens at a lower threshold, which makes it relevant to glucose homeostasis from day-to-day. Several SGLT2 inhibitors are now approved glucose lowering agents for individuals with type 2 diabetes and preserved kidney function. By inducing glucosuria, these drugs improve glycaemic control in all stages of type 2 diabetes, while their risk of causing hypoglycaemia is low because they naturally stop working when the filtered glucose load falls below ∼80 g/day and they do not otherwise interfere with metabolic counterregulation. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. Because SGLT2 reabsorbs sodium along with glucose, SGLT2 blockers are natriuretic and antihypertensive. Also, because they work in the proximal tubule, SGLT2 inhibitors increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure. This mitigates glomerular hyperfiltration, reduces the kidney's demand for oxygen and lessens albuminuria. For reasons that are less well understood, SGLT2 inhibitors are also uricosuric. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.
- Published
- 2016
11. Effects of Acute SGLT2 Blockade and Dietary NaCl on Glomerular Hemodynamics in Diabetic Rats
- Author
-
Scott C. Thomson and Volker Vallon
- Subjects
medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Genetics ,medicine ,business ,Molecular Biology ,Biochemistry ,Biotechnology ,Blockade ,Glomerular hemodynamics - Published
- 2020
12. Renal Effects of Incretin-Based Diabetes Therapies: Pre-clinical Predictions and Clinical Trial Outcomes
- Author
-
Scott C. Thomson and Volker Vallon
- Subjects
endocrine system ,Endocrinology, Diabetes and Metabolism ,Renal function ,Incretin ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Kidney ,Bioinformatics ,Incretins ,Article ,Diabetic nephropathy ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Diabetes Mellitus ,Internal Medicine ,medicine ,Humans ,Dipeptidyl peptidase-4 ,Clinical Trials as Topic ,business.industry ,digestive, oral, and skin physiology ,Hemodynamics ,medicine.disease ,Clinical trial ,Treatment Outcome ,medicine.anatomical_structure ,Albuminuria ,medicine.symptom ,business - Abstract
PURPOSE OF REVIEW: The purpose of this review is to correlate predictions based on pre-clinical data with outcomes from clinical trials that examine the effects of incretin-based diabetes treatments on the kidney. The incretin-based treatments include agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of the enzyme, dipeptidyl peptidase-4 (DPP-4). In addition, what is known about the incretin-based therapies will be compared to what is known about the renal effects of SGLT2 inhibitors. RECENT FINDINGS: Large-scale clinical trials have shown that SGLT2 inhibitors reduce albuminuria and preserve estimated glomerular filtration rate (eGFR) in patients with diabetic nephropathy. A concise and plausible hemodynamic mechanism is supported by pre-clinical research on the physiology and pharmacology of SGLT2. Large-scale clinical trials have shown that incretin-based therapies mitigate albuminuria but have not shown beneficial effects on eGFR. Research on the incretin-based therapies has yielded a diverse array of direct effects throughout the body, which fuels speculation as to how these drugs might benefit the diabetic kidney and affect its function(s). But in vivo experiments have yet to confirm that the proposed mechanisms underlying emergent phenomena, such as proximal tubular fluid reabsorption, are the ones predicted by cell and molecular experiments. SUMMARY: There may be salutary effects of incretin-based treatments on the diabetic kidney, but the system is complex and not amenable to simple explanation or prior prediction. This contrasts with the renal effects of SGLT2 inhibitors, which can be explained concisely.
- Published
- 2018
13. Dynamic Renal Blood Flow Autoregulation During Recovery From Acute Kidney Injury (AKI)
- Author
-
Hai Pham, Prabhleen Singh, and Scott C. Thomson
- Subjects
medicine.medical_specialty ,business.industry ,Acute kidney injury ,medicine.disease ,Biochemistry ,Internal medicine ,Renal blood flow ,Genetics ,Cardiology ,Medicine ,Autoregulation ,business ,Molecular Biology ,Biotechnology - Published
- 2018
14. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia
- Author
-
Takahiro Masuda, Timo Rieg, David R. Powell, Eric Mayoux, Hermann Koepsell, Kenneth A. Platt, Maria Gerasimova, Scott C. Thomson, and Volker Vallon
- Subjects
Blood Glucose ,Male ,Glycosuria ,medicine.medical_specialty ,Physiology ,Drinking ,Biological Transport, Active ,Kidney ,Kidney Tubules, Proximal ,Eating ,Mice ,Sodium-Glucose Transporter 1 ,Glucosides ,Sodium-Glucose Transporter 2 ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Benzhydryl Compounds ,Sodium-Glucose Transporter 2 Inhibitors ,Mice, Knockout ,Dose-Response Relationship, Drug ,Chemistry ,digestive, oral, and skin physiology ,Glucose transporter ,Articles ,medicine.disease ,Renal glucose reabsorption ,Urodynamics ,Glucose ,Endocrinology ,medicine.anatomical_structure ,Mediated transport ,Female ,medicine.symptom ,Cotransporter - Abstract
In the kidney, the sodium-glucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and ∼3% of fractional glucose reabsorption (FGR), respectively. However, euglycemic humans treated with an SGLT2 inhibitor maintain an FGR of 40–50%, mimicking values in Sglt2 knockout mice. Here, we show that oral gavage with a selective SGLT2 inhibitor (SGLT2-I) dose dependently increased urinary glucose excretion (UGE) in wild-type (WT) mice. The dose-response curve was shifted leftward and the maximum response doubled in Sglt1 knockout (Sglt1−/−) mice. Treatment in diet with the SGLT2-I for 3 wk maintained 1.5- to 2-fold higher urine glucose/creatinine ratios in Sglt1−/− vs. WT mice, associated with a temporarily greater reduction in blood glucose in Sglt1−/− vs. WT after 24 h (−33 vs. −11%). Subsequent inulin clearance studies under anesthesia revealed free plasma concentrations of the SGLT2-I (corresponding to early proximal concentration) close to the reported IC50 for SGLT2 in mice, which were associated with FGR of 64 ± 2% in WT and 17 ± 2% in Sglt1−/−. Additional intraperitoneal application of the SGLT2-I (maximum effective dose in metabolic cages) increased free plasma concentrations ∼10-fold and reduced FGR to 44 ± 3% in WT and to −1 ± 3% in Sglt1−/−. The absence of renal glucose reabsorption was confirmed in male and female Sglt1/Sglt2 double knockout mice. In conclusion, SGLT2 and SGLT1 account for renal glucose reabsorption in euglycemia, with 97 and 3% being reabsorbed by SGLT2 and SGLT1, respectively. When SGLT2 is fully inhibited by SGLT2-I, the increase in SGLT1-mediated glucose reabsorption explains why only 50–60% of filtered glucose is excreted.
- Published
- 2014
15. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice
- Author
-
Takahiro Masuda, Scott C. Thomson, Joseph Satriano, Timo Rieg, Volker Vallon, Maria Gerasimova, Hermann Koepsell, Eric Mayoux, and Michael Rose
- Subjects
Blood Glucose ,medicine.medical_specialty ,Physiology ,Blotting, Western ,Kidney Glomerulus ,Drinking ,Renal function ,Blood Pressure ,Mice, Inbred Strains ,Kidney ,Real-Time Polymerase Chain Reaction ,Eating ,Mice ,chemistry.chemical_compound ,Sodium-Glucose Transporter 1 ,Glucosides ,Sodium-Glucose Transporter 2 ,Heart Rate ,Internal medicine ,Adipocytes ,Diabetes Mellitus ,medicine ,Empagliflozin ,Albuminuria ,Animals ,Diabetic Nephropathies ,Benzhydryl Compounds ,Sodium-Glucose Transporter 2 Inhibitors ,Inflammation ,Creatinine ,Chemistry ,Articles ,Renal glucose reabsorption ,Endocrinology ,medicine.anatomical_structure ,Hyperglycemia ,medicine.symptom ,SGLT2 Inhibitor ,Biomarkers ,Glomerular hyperfiltration ,Glomerular Filtration Rate - Abstract
Our previous work has shown that gene knockout of the sodium-glucose cotransporter SGLT2 modestly lowered blood glucose in streptozotocin-diabetic mice (BG; from 470 to 300 mg/dl) and prevented glomerular hyperfiltration but did not attenuate albuminuria or renal growth and inflammation. Here we determined effects of the SGLT2 inhibitor empagliflozin (300 mg/kg of diet for 15 wk; corresponding to 60–80 mg·kg−1·day−1) in type 1 diabetic Akita mice that, opposite to streptozotocin-diabetes, upregulate renal SGLT2 expression. Akita diabetes, empagliflozin, and Akita + empagliflozin similarly increased renal membrane SGLT2 expression (by 38–56%) and reduced the expression of SGLT1 (by 33–37%) vs. vehicle-treated wild-type controls (WT). The diabetes-induced changes in SGLT2/SGLT1 protein expression are expected to enhance the BG-lowering potential of SGLT2 inhibition, and empagliflozin strongly lowered BG in Akita (means of 187–237 vs. 517–535 mg/dl in vehicle group; 100–140 mg/dl in WT). Empagliflozin modestly reduced GFR in WT (250 vs. 306 μl/min) and completely prevented the diabetes-induced increase in glomerular filtration rate (GFR) (255 vs. 397 μl/min). Empagliflozin attenuated increases in kidney weight and urinary albumin/creatinine ratio in Akita in proportion to hyperglycemia. Empagliflozin did not increase urinary glucose/creatinine ratios in Akita, indicating the reduction in filtered glucose balanced the inhibition of glucose reabsorption. Empagliflozin attenuated/prevented the increase in systolic blood pressure, glomerular size, and molecular markers of kidney growth, inflammation, and gluconeogenesis in Akita. We propose that SGLT2 inhibition can lower GFR independent of reducing BG (consistent with the tubular hypothesis of diabetic glomerular hyperfiltration), while attenuation of albuminuria, kidney growth, and inflammation in the early diabetic kidney may mostly be secondary to lower BG.
- Published
- 2014
16. Renal Effects of Sodium-Glucose Co-Transporter Inhibitors
- Author
-
Volker Vallon and Scott C. Thomson
- Subjects
Kidney Disease ,Tubuloglomerular feedback ,Cardiorespiratory Medicine and Haematology ,030204 cardiovascular system & hematology ,Pharmacology ,Kidney ,Kidney Tubules, Proximal ,0302 clinical medicine ,Proximal tubule ,Medicine ,Renal Insufficiency ,030212 general & internal medicine ,Chronic ,Kidney Tubules, Distal ,biology ,Sodium-Hydrogen Exchanger 3 ,Reabsorption ,Diabetes ,Proximal ,General Medicine ,Nitric oxide synthase ,Kidney Tubules ,medicine.anatomical_structure ,Hypertension ,Disease Progression ,Cardiology ,Cardiology and Cardiovascular Medicine ,Type 2 ,Glomerular Filtration Rate ,medicine.medical_specialty ,Renal and urogenital ,Renal function ,030209 endocrinology & metabolism ,Article ,Renal Circulation ,03 medical and health sciences ,Sodium-Glucose Transporter 1 ,Sodium-Glucose Transporter 2 ,Internal medicine ,Glomerular filtration ,Diabetes Mellitus ,Humans ,Renal Insufficiency, Chronic ,Diabetic kidney disease ,Sodium-Glucose Transporter 2 Inhibitors ,Metabolic and endocrine ,Nutrition ,Distal ,business.industry ,Type 2 Diabetes Mellitus ,medicine.disease ,Diabetes Mellitus, Type 2 ,Cardiovascular System & Hematology ,biology.protein ,Macula densa ,Nitric Oxide Synthase ,business ,Kidney disease - Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.
- Published
- 2019
17. Abstract 104: Dynamic Autoregulation of Glomerular Capillary Pressure
- Author
-
Scott C. Thomson
- Subjects
medicine.medical_specialty ,Glomerular capillary pressure ,urogenital system ,Chemistry ,Internal medicine ,Internal Medicine ,Cardiology ,medicine ,Autoregulation - Abstract
It is generally accepted that renal blood flow (RBF) autoregulation is mediated by myogenic and tubuloglomerular feedback responses acting on the pre-glomerular resistance. If this is so, then autoregulation of RBF and glomerular capillary pressure (PGC) should change in the same direction throughout an autoregulatory step response. We computed autoregulatory step responses from time series recordings of arterial blood pressure (BP) and RBF (Transonics) blood flow or tubular stop-flow pressure (micropuncture), which is a surrogate for PGC in Wistar-Froemter rats fed for one week on low or high salt diets (n=6-10 ). Autoregulatory step responses were generated from time series by an algorithm that treats BP as a leading indicator of RBF or PGC and uses the projection theorem to solve for the impulse response which is integrated to obtain the step response. Step responses shown in the figure represent the uncompensated changes in RBF and PGC (mean + SEM) following a 1 mmHg BP step. The data clearly reveal that the time courses of RBF and PGC differ such that changes in RBF cannot predict changes in PGC. This implies that the renal hemodynamic response to a blood pressure disturbance is not confined to the pre-glomerular resistance. Furthermore, the participation of post-glomerular resistance in the autoregulatory response is sensitive to dietary salt such that PGC is more sensitive to BP on low salt diet.
- Published
- 2016
18. Biophysics of Glomerular Filtration
- Author
-
Scott C. Thomson and Roland C. Blantz
- Subjects
medicine.anatomical_structure ,Chemistry ,Kidney Glomerulus ,medicine ,Biological Transport, Active ,Humans ,Renal function ,Physiology ,Neuroscience ,Renal Circulation ,Podocyte - Abstract
Enlightened by William Bowman’s depiction of the anatomy in 1842, Carl Ludwig immediately proposed glomerular filtration as a physical process. Nuances of this process have come to light in a rather orderly progression over the past 150 years with essential contributions from clearance methods, renal micropuncture, physical theories of nonequilibrium thermodynamics and electrical double layers, morphometry, and mathematics. Herein, we describe that progression of knowledge. Ongoing work pertains to the nature, location, and efficiency of the barrier to protein sieving, induction of endothelial fenestrae by growth factors from the podocyte, and potential resistance faced by filtrate exiting the subpodocyte space. Published 2012 Compr Physiol 2:1671-1699, 2012.
- Published
- 2012
19. Renal Function in Diabetic Disease Models: The Tubular System in the Pathophysiology of the Diabetic Kidney
- Author
-
Scott C. Thomson and Volker Vallon
- Subjects
medicine.medical_specialty ,Physiology ,Kidney Glomerulus ,Glucose Transport Proteins, Facilitative ,Renal function ,Sodium Chloride ,Article ,Kidney Tubules, Proximal ,Diabetic nephropathy ,Electrolytes ,Internal medicine ,Diabetes mellitus ,Animals ,Humans ,Medicine ,Diabetic Nephropathies ,Tubuloglomerular feedback ,Feedback, Physiological ,Glucose Transporter Type 2 ,Kidney ,urogenital system ,business.industry ,Reabsorption ,Sodium ,Hypertrophy ,medicine.disease ,Glucose ,Kidney Tubules ,Endocrinology ,medicine.anatomical_structure ,Disease Progression ,business ,Glomerular hyperfiltration ,Glomerular Filtration Rate - Abstract
Diabetes mellitus affects the kidney in stages. At the onset of diabetes mellitus, in a subset of diabetic patients the kidneys grow large, and glomerular filtration rate (GFR) becomes supranormal, which are risk factors for developing diabetic nephropathy later in life. This review outlines a pathophysiological concept that focuses on the tubular system to explain these changes. The concept includes the tubular hypothesis of glomerular filtration, which states that early tubular growth and sodium-glucose cotransport enhance proximal tubule reabsorption and make the GFR supranormal through the physiology of tubuloglomerular feedback. The diabetic milieu triggers early tubular cell proliferation, but the induction of TGF-β and cyclin-dependent kinase inhibitors causes a cell cycle arrest and a switch to tubular hypertrophy and a senescence-like phenotype. Although this growth phenotype explains unusual responses like the salt paradox of the early diabetic kidney, the activated molecular pathways may set the stage for tubulointerstitial injury and diabetic nephropathy.
- Published
- 2012
20. Cardiovascular and renal benefits of SGLT2 inhibition: insights from CANVAS
- Author
-
Scott C. Thomson and Volker Vallon
- Subjects
Canagliflozin ,medicine.medical_specialty ,Kidney ,Renal sodium reabsorption ,urogenital system ,business.industry ,Sodium ,Type 2 Diabetes Mellitus ,chemistry.chemical_element ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Nephrology ,Diabetes mellitus ,Internal medicine ,medicine ,In patient ,business ,Beneficial effects ,medicine.drug - Abstract
Inhibitors of renal sodium/glucose cotransporter 2 (SGLT2) are new anti-hyperglycaemic drugs that reduce proximal tubular glucose and sodium reabsorption. The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program is the second major trial to demonstrate beneficial effects of SGLT2 inhibitors on the kidney and cardiovascular system in patients with type 2 diabetes mellitus.
- Published
- 2017
21. 2017 Robert W. Berliner Award for Excellence in Renal Physiology
- Author
-
Scott C. Thomson and Volker Vallon
- Subjects
Gerontology ,Physiology ,business.industry ,Excellence ,media_common.quotation_subject ,Renal physiology ,Medicine ,business ,Management ,media_common - Published
- 2017
22. Renal protection in chronic kidney disease: hypoxia-inducible factor activation vs. angiotensin II blockade
- Author
-
Mary Ann K. Arndt, Tong Tang, Joseph Satriano, Prabhleen Singh, Roland C. Blantz, Timo Rieg, Scott C. Thomson, and Aihua Deng
- Subjects
Male ,medicine.medical_specialty ,Physiology ,Renal function ,Kidney ,Proliferating Cell Nuclear Antigen ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Carbonic Anhydrase IX ,Carbonic Anhydrases ,Glucose Transporter Type 1 ,Chemistry ,Angiotensin II ,Cobalt ,Articles ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Amino Acids, Dicarboxylic ,Rats ,Blockade ,Endocrinology ,medicine.anatomical_structure ,Hypoxia-inducible factors ,Erythropoietin ,Enzyme Induction ,Renal blood flow ,Kidney Failure, Chronic ,Kidney disease ,medicine.drug - Abstract
The 5/6thnephrectomy or ablation/infarction (A/I) preparation has been used as a classic model of chronic kidney disease (CKD). We observed increased kidney oxygen consumption (QO2) and altered renal hemodynamics in the A/I kidney that were normalized after combined angiotensin II (ANG II) blockade. Studies suggest hypoxia inducible factor as a protective influence in A/I. We induced hypoxia-inducible factor (HIF) and HIF target proteins by two different methods, cobalt chloride (CoCl2) and dimethyloxalyglycine (DMOG), for the first week after creation of A/I and compared the metabolic and renal hemodynamic outcomes to combined ANG II blockade. We also examined the HIF target proteins expressed by using Western blots and real-time PCR. Treatment with DMOG, CoCl2, and ANG II blockade normalized kidney oxygen consumption factored by Na reabsorption and increased both renal blood flow and glomerular filtration rate. At 1 wk, CoCl2and DMOG increased kidney expression of HIF by Western blot. In the untreated A/I kidney, VEGF, heme oxygenase-1, and GLUT1 were all modestly increased. Both ANG II blockade and CoCl2therapy increased VEGF and GLUT1 but the cobalt markedly so. ANG II blockade decreased heme oxygenase-1 expression while CoCl2increased it. By real-time PCR, erythropoietin and GLUT1 were only increased by CoCl2therapy. Cell proliferation was modestly increased by ANG II blockade but markedly after cobalt therapy. Metabolic and hemodynamic abnormalities were corrected equally by ANG II blockade and HIF therapies. However, the molecular patterns differed significantly between ANG II blockade and cobalt therapy. HIF induction may prove to be protective in this model of CKD.
- Published
- 2010
23. Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes
- Author
-
Joseph Satriano, Roland C. Blantz, Volker Vallon, Scott C. Thomson, Aihua Deng, Kumar Sharma, and Hadi Mansoury
- Subjects
Male ,Senescence ,medicine.medical_specialty ,Time Factors ,Physiology ,Urinary system ,Biology ,Diabetes Mellitus, Experimental ,Kidney Tubules, Proximal ,Rats, Sprague-Dawley ,Pathogenesis ,Diabetic nephropathy ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Sodium Chloride, Dietary ,Cellular Senescence ,Kidney ,Growth, Differentiation, and Apoptosis ,Biological Transport ,Opossums ,Cell Biology ,beta-Galactosidase ,medicine.disease ,Rats ,Oxidative Stress ,Phenotype ,medicine.anatomical_structure ,Endocrinology ,Cell aging ,Glomerular hyperfiltration - Abstract
Diabetic nephropathy is the commonest cause of end-stage renal disease. Inordinate kidney growth and glomerular hyperfiltration at the very early stages of diabetes are putative antecedents to this disease. The kidney is the only organ that grows larger with the onset of diabetes mellitus, yet there remains confusion about the mechanism and significance of this growth. Here we show that kidney proximal tubule cells in culture transition to senescence in response to oxidative stress. We further determine the temporal expression of G1phase cell cycle components in rat kidney cortex at days 4 and 10 of streptozotocin diabetes to evaluate changes in this growth response. In diabetic rats we observe increases in kidney weight-to-body weight ratios correlating with increases in expression of the growth-related proteins in the kidney at day 4 after induction of diabetes. However, at day 10 we find a decrease in this profile in diabetic animals coincident with increased cyclin-dependent kinase inhibitor expressions. We observe no change in caspase-3 expression in the diabetic kidneys at these early time points; however, diabetic animals demonstrate reduced kidney connexin 43 and increased plasminogen activator inhibitor-1 expressions and increased senescence-associated β-galactosidase activity in cortical tubules. In summary, diabetic kidneys exhibit an early temporal induction of growth phase components followed by their suppression concurrent with the induction of cyclin-dependent kinase inhibitors and markers of senescence. These data delineate a phenotypic change in cortical tubules early in the pathogenesis of diabetes that may contribute to further downstream complications of the disease.
- Published
- 2010
24. Adenosine A1 Receptors Determine Glomerular Hyperfiltration and the Salt Paradox in Early Streptozotocin Diabetes Mellitus
- Author
-
Roland C. Blantz, Timo Rieg, Volker Vallon, Scott C. Thomson, Joseph Satriano, and Jana Schroth
- Subjects
medicine.medical_specialty ,urogenital system ,Physiology ,Renal glomerulus ,business.industry ,Renal function ,General Medicine ,urologic and male genital diseases ,Streptozotocin ,medicine.disease ,Adenosine ,female genital diseases and pregnancy complications ,Diabetic nephropathy ,Endocrinology ,Nephrology ,Physiology (medical) ,Internal medicine ,Diabetes mellitus ,medicine ,sense organs ,business ,Glomerular hyperfiltration ,medicine.drug ,Tubuloglomerular feedback - Abstract
Background: In early type 1 diabetes mellitus, changes in proximal reabsorption influence glomerular filtration rate (GFR) through tubuloglomerular feedback (TGF). Due to TGF, a primary increase in proximal reabsorption causes early diabetic hyperfiltration, while a heightened sensitivity of the proximal tubule to dietary salt leads to the so-called salt paradox, where a change in dietary salt causes a reciprocal change in GFR (‘tubulocentric principle’). Here, experiments were performed in adenosine A1 receptor knockout mice (A1R–/–), which lack an immediate TGF response, to determine whether A1Rs are essential for early diabetic hyperfiltration and the salt paradox. Methods: GFR was measured by inulin disappearance in conscious A1R–/– and wild-type (WT) mice after 4 weeks of streptozotocin diabetes on a control NaCl diet (1%), and measurements were repeated after 6 days of equilibration on a low-NaCl (0.1%) or a high-NaCl (4%) diet. Results: A1R–/– and WT were similar with respect to blood glucose, dietary intakes and body weight changes on a given diet. Diabetic hyperfiltration occurred in WT, but was blunted in A1R–/–. A reciprocal relationship between GFR and dietary salt was found in WT diabetics, but not A1R–/– diabetics or nondiabetics of either strain. Conclusion: A1Rs determine glomerular hyperfiltration and the salt paradox in early diabetes, which is consistent with the tubulocentric principle.
- Published
- 2009
25. <scp>l</scp>-arginine-induced glomerular hyperfiltration response: the roles of insulin and ANG II
- Author
-
Scott C. Thomson, Karen A. Munger, Roland C. Blantz, Mario Ruiz, Prabhleen Singh, and Francis B. Gabbai
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Arginine ,Physiology ,medicine.medical_treatment ,Kidney Glomerulus ,Renal function ,Blood Pressure ,Vasodilation ,Nitric Oxide ,Octreotide ,Nitric oxide ,Kidney Tubules, Proximal ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Insulin ,Rats, Wistar ,Kidney ,Nitrates ,urogenital system ,Chemistry ,Angiotensin II ,Nephrons ,Rats ,Endocrinology ,medicine.anatomical_structure ,Hematocrit ,Glomerular hyperfiltration ,Glomerular Filtration Rate - Abstract
Infusion of l-arginine produces an increase in glomerular filtration via kidney vasodilation, correlating with increased kidney excretion of nitric oxide (NO) metabolites, but the specific underlying mechanisms are unknown. We utilized clearance and micropuncture techniques to examine the whole kidney glomerular filtration rate (GFR) and single nephron GFR (SNGFR) responses to 1) l-arginine (ARG), 2) ARG+octreotide (OCT) to block insulin release, 3) ARG+OCT+insulin (INS) infusion to duplicate ARG-induced insulin levels, and 4) losartan (LOS), an angiotensin AT-1 receptor blocker, +ARG+OCT. ARG infusion increased GFR, while increasing insulin levels. OCT coinfusion prevented this increase in GFR, but with insulin infusion to duplicate ARG induced rise in insulin, the GFR response was restored. Identical insulin levels in the absence of ARG had no effect on GFR. In contrast to ARG infusion alone, coinfusion of OCT with ARG reduced proximal tubular fractional and absolute reabsorption potentially activating tubuloglomerular feedback. Losartan infusion, in addition to ARG and OCT (LOS+ARG+OCT), restored the increase in both SNGFR and proximal tubular reabsorption, without increasing insulin levels. In conclusion, 1) hyperfiltration responses to ARG require the concurrent, modest, permissive increase in insulin; 2) inhibition of insulin release after ARG reduces proximal reabsorption and prevents the hyperfiltration response; and 3) inhibition of ANG II activity restores the hyperfiltration response, maintains parallel increases in proximal reabsorption, and overrides the arginine/octreotide actions.
- Published
- 2008
26. The Effect of KW-3902, an Adenosine A1 Receptor Antagonist, on Renal Function and Renal Plasma Flow in Ambulatory Patients With Heart Failure and Renal Impairment
- Author
-
Dinesh K. Gupta, Scott C. Thomson, Howard C. Dittrich, Thomas C. Dowling, Janice Callahan, and Terrence C. Hack
- Subjects
medicine.medical_specialty ,Kidney ,business.industry ,Furosemide ,Renal function ,medicine.disease ,Rolofylline ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Internal medicine ,Heart failure ,Renal physiology ,Renal blood flow ,medicine ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Tubuloglomerular feedback ,medicine.drug - Abstract
Background The kidney is the only organ in which adenosine is a paracrine vasoconstrictor. This raises the possibility of using adenosine A 1 receptor (AA 1 R) antagonists to selectively vasodilate the kidney in conditions, such as congestive heart failure, in which a selective decrease in renal vascular resistance would be salutary. The present study was undertaken to test the effectiveness of an AA 1 R antagonist as a renal vasodilator in patients with reduced kidney function superimposed on congestive heart failure. Methods and Results A randomized, double-blind, placebo-controlled, two-way crossover study was conducted in 32 outpatients with congestive heart failure and renal impairment (median glomerular filtration rate [GFR] 50 mL/min). Baseline GFR and renal plasma flow were assessed by iothalamate and para-amino-hippurate clearances, respectively, 3 hours before treatment. Subjects then received furosemide administered intravenously along with the AA 1 R antagonist, KW-3902 (rolofylline), or placebo. Clearance measurements were repeated, at intervals, throughout 8 hours beginning with the administration of the study drug. After a washout period of 3 to 8 days, subjects returned to undergo the crossover portion of the study. After the patients received KW-3902, GFR increased by 32% ( P P P Conclusions AA 1 R activity contributes substantially to renal vascular tone in ambulatory patients with chronic congestive heart failure and impaired kidney function. Blockade of these receptors vasodilates the kidney and increases GFR. The increase in GFR seems to persist several days longer than predicted by pharmacokinetics, suggesting a resetting of one or more controllers among the complex network of physical and biological processes that interact to determine the kidney function. There may be short- or long-term benefits of using AA 1 R antagonists to improve kidney function in patients with congestive heart failure.
- Published
- 2007
27. Central European Meeting on Hypertension and Cardiovascular Disease Prevention
- Author
-
Cynthia M. Miracle, Patricia R. Wahl, Oliver Vonend, Mehmet Kanbay, Adrian Covic, Ali Akcay, Roland C. Blantz, Feridun Karakurt, Brigitta Rumberger, Scott C. Thomson, Peter Gerke, Krystyna Pawlak, J.S. Malyszko, Clemens Kreutz, Johannes Donauer, Michal Mysliwiec, Hanna Bachórzewska-Gajewska, E. Sitniewska, Sławomir Dobrzycki, Astrid Starke, Faruk Turgut, Bunyamin Isik, Ying Waeckerle-Men, Timo Rieg, Bernhard Banas, Jacek S. Malyszko, Stephan R. Orth, Jens Timmer, Gerd Walz, Rabia Alkan, Romana Rysava, Volker Vallon, Rudolf P. Wüthrich, Ramazan Yigitoglu, Kerstin Amann, Jochen Wilpert, Eberhard Ritz, Rolf Rohrbach, Günter Schiele, Maciej Szmitkowski, and S. Lawnicki
- Subjects
medicine.medical_specialty ,Nephrology ,business.industry ,medicine ,Disease prevention ,General Medicine ,Cardiology and Cardiovascular Medicine ,Intensive care medicine ,business - Published
- 2007
28. Combined Effects of Carbonic Anhydrase Inhibitor and Adenosine A1 Receptor Antagonist on Hemodynamic and Tubular Function in the Kidney
- Author
-
Volker Vallon, Timo Rieg, Scott C. Thomson, Cynthia M. Miracle, and Roland C. Blantz
- Subjects
medicine.medical_specialty ,Kidney ,genetic structures ,biology ,urogenital system ,Chemistry ,medicine.drug_class ,Renal function ,General Medicine ,urologic and male genital diseases ,Adenosine receptor ,female genital diseases and pregnancy complications ,Benzolamide ,Adenosine A1 receptor ,Endocrinology ,medicine.anatomical_structure ,Nephrology ,Internal medicine ,Carbonic anhydrase ,medicine ,biology.protein ,Carbonic anhydrase inhibitor ,sense organs ,Cardiology and Cardiovascular Medicine ,Tubuloglomerular feedback - Abstract
Background: Carbonic anhydrase inhibitors (CAI) reduce proximal reabsorption, activating tubuloglomerular feedback (TGF) and reducing glomerular filtration rate (GFR). Adenosine A1 receptors (A1R) mediate the TGF response and stimulate proximal reabsorption. Methods: Clearance and micropuncture studies were performed in Wistar rats to determine whether blockade of A1R (KW3902 0.3 mg/kg i.v.) would prevent CAI (benzolamide 5 mg/kg i.v.) from lowering GFR, whether CAI and KW3902 exert additive effects on sodium excretion, and to what extent such interactions depend on events in the glomerulus, proximal tubule, or distal nephron. Results: KW3902 raised GFR and prevented CAI from lowering GFR. KW3902 and CAI caused additive diuresis and natriuresis. KW3902 and CAI increased lithium clearance, but their effects were redundant. CAI increased the dependence of proximal reabsorption on active chloride transport. KW3902, alone, did likewise, but to a lesser extent than CAI. Adding KW3902 to CAI lessened the shift toward active chloride transport. Conclusions: The data reveal that A1R mediate glomerular vascular resistance whether or not TGF is activated, that additive effects of CAI and KW3902 on salt excretion occur, in part, because KW3902 inhibits reabsorption downstream from the macula densa, and that KW3902 likely inhibits proximal reabsorption by interfering with apical sodium-hydrogen exchange.
- Published
- 2007
29. RBF Autoregulatory Dynamics in a Virtual Step Response
- Author
-
Hai Pham, Scott C. Thomson, and Prabhleen Singh
- Subjects
Step response ,Control theory ,Computer science ,Dynamics (mechanics) ,Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2015
30. Increased Oxygen Consumption and Basal Metabolism of the Proximal Tubule in Early Diabetes
- Author
-
Ser Khang, Joanna Thomas, Prabhleen Singh, Hai Pham, and Scott C. Thomson
- Subjects
medicine.medical_specialty ,Chemistry ,Sodium ,chemistry.chemical_element ,Hypoxia (medical) ,medicine.disease ,Biochemistry ,Oxygen ,medicine.anatomical_structure ,Endocrinology ,Diabetes mellitus ,Internal medicine ,Basal metabolic rate ,Genetics ,medicine ,Proximal tubule ,medicine.symptom ,Molecular Biology ,Biotechnology - Abstract
Increased renal oxygen consumption (QO2) and hypoxia have been observed in early diabetes, but underlying mechanisms are still being investigated. Nearly 80% of QO2 is used for active sodium transp...
- Published
- 2015
31. Kidney oxygen consumption, carbonic anhydrase, and proton secretion
- Author
-
Aihua Deng, Scott C. Thomson, Mark Lortie, Karen A. Munger, Joseph Satriano, Blantz Roland, Francis B. Gabbai, and Cynthia M. Miracle
- Subjects
Male ,medicine.medical_specialty ,Sodium-Hydrogen Exchangers ,Physiology ,chemistry.chemical_element ,Oxygen ,Kidney Tubules, Proximal ,Benzolamide ,Oxygen Consumption ,Internal medicine ,Carbonic anhydrase ,medicine ,Animals ,Rats, Wistar ,Carbonic Anhydrases ,Kidney ,biology ,Renal sodium reabsorption ,Chemistry ,Sodium ,Hydrogen-Ion Concentration ,Adenosine ,Rats ,Endocrinology ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,Protons ,Autacoid ,medicine.drug ,Hormone - Abstract
Oxygen consumed by the kidney (QO2) is primarily obligated to sodium reabsorption (TNa). The relationship of QO2to TNa(QO2/TNa) may be altered by hormones and autacoids. To examine whether QO2/TNadepends on the mechanism of sodium reabsorption, we first evaluated the effects on QO2and QO2/TNaof benzolamide (BNZ), a proximal diuretic that works by inhibiting membrane carbonic anhydrase. During BNZ infusion in anesthetized rats, QO2increased by 50% despite a 25% decline in TNa. However, BNZ failed to increase QO2/TNawhen given along with the adenosine A1 receptor blocker, DPCPX, which inhibits basolateral Na-bicarbonate cotransport (NBC1), or EIPA, which inhibits sodium-hydrogen exchange (NHE). Incubating freshly harvested rat proximal tubules with BNZ also caused QO2to increase by 62%, an effect that was prevented by blocking the apical NHE3 with S3226. Blocking NBC1 or NHE3 in the proximal tubule will have opposite effects on cell pH, but both maneuvers should reduce active chloride transport. In conclusion, inhibiting membrane carbonic anhydrase in the proximal tubule increases QO2and reduces the energy efficiency of sodium reabsorption by the kidney. This is not purely due to shifting the burden of reabsorption to a more expensive site downstream from the proximal tubule. Instead, increased cost may be incurred within the proximal tubule as the result of increased active chloride transport.
- Published
- 2006
32. An unexpected role for angiotensin II in the link between dietary salt and proximal reabsorption
- Author
-
Blantz Roland, Lucinda M. Wead, Aihua Deng, Kerstin Richter, Volker Vallon, and Scott C. Thomson
- Subjects
Male ,medicine.medical_specialty ,Tubular fluid ,Nephron ,Absorption ,Kidney Tubules, Proximal ,Internal medicine ,medicine ,Animals ,Homeostasis ,Rats, Wistar ,Tubuloglomerular feedback ,Angiotensin II receptor type 1 ,Chemistry ,Angiotensin II ,Antagonist ,Sodium, Dietary ,Nephrons ,General Medicine ,Rats ,Losartan ,medicine.anatomical_structure ,Endocrinology ,Research Article ,medicine.drug - Abstract
We set out to confirm the long-held, but untested, assumption that dietary salt affects proximal reabsorption through reciprocal effects on the renin-angiotensin system in a way that facilitates salt homeostasis. Wistar rats were fed standard or high-salt diets for 7 days and then subjected to renal micropuncture for determination of single-nephron GFR (SNGFR) and proximal reabsorption. The tubuloglomerular feedback (TGF) system was used as a tool to manipulate SNGFR in order to distinguish primary changes in net proximal reabsorption (Jprox) from changes due to glomerulotubular balance. The influence of Ang II over Jprox was determined by the sensitivity of Jprox to the AT1 receptor antagonist, losartan. Plasma, whole kidneys, and fluid from midproximal tubules were assayed for Ang II content by radioimmunoassay. In rats on the standard diet, losartan reduced Jprox by 25% and reduced the maximum range of the TGF response by 50%. The high-salt diet suppressed plasma and whole-kidney Ang II levels. But the high-salt diet failed to reduce the impact of losartan on Jprox or the TGF response and actually caused tubular fluid Ang II content to increase. The persistent effect of Ang II on Jprox prevented a major rise in late proximal flow rate in response to the high-salt diet. These observations challenge the traditional model and indicate that the role of proximal tubular Ang II in salt-replete rats is to stabilize nephron function rather than to contribute to salt homeostasis.
- Published
- 2006
33. Oxygen consumption in the kidney: Effects of nitric oxide synthase isoforms and angiotensin II
- Author
-
Scott C. Thomson, Aihua Deng, Blantz Roland, Karen A. Munger, Joseph Satriano, Mark Lortie, Jorge M. Suarez, and Cynthia M. Miracle
- Subjects
Male ,kidney ,medicine.medical_specialty ,Angiotensin receptor ,Nerve Tissue Proteins ,Nitric Oxide Synthase Type I ,NOS and NOS-1 ,Losartan ,Renal Circulation ,Nitric oxide ,Kidney Tubules, Proximal ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Enzyme Inhibitors ,Rats, Wistar ,Kidney ,omega-N-Methylarginine ,biology ,Renal sodium reabsorption ,Chemistry ,Angiotensin II ,Sodium ,oxygen consumption ,Rats ,Nitric oxide synthase ,medicine.anatomical_structure ,Endocrinology ,angiotensin receptor blockade ,Nephrology ,Renal blood flow ,cardiovascular system ,biology.protein ,Nitric Oxide Synthase ,Energy Metabolism ,Angiotensin II Type 1 Receptor Blockers ,Glomerular Filtration Rate ,medicine.drug - Abstract
Oxygen consumption in the kidney: Effects of nitric oxide synthase isoforms and angiotensin II. Background Oxygen mitochondrial effects consumption by the kidney (Qo 2 ), is linearly related to sodium reabsorption (T na ), but recent studies suggest this relationship is variable and that metabolic efficiency (Qo 2 /T na ) in kidney is regulated by hormonal factors. In the dog, nonselective inhibitors of nitric oxide synthase (NOS) increase Qo 2 and Qo 2 /T na . Glomerular hemodynamic and reabsorptive consequences of NOS inhibition require angiotensin II (Ang II), implying an antagonistic relationship between nitric oxide and Ang II. Effects of NOS inhibition in the rat, the role of Ang II and the responsible NOS isoform have not been elucidated. Methods Kidney blood flow [renal blood flow (RBF)], glomerular filtration rate (GFR), and Qo 2 /T na were measured before and during intravenous administration of N G -monomethyl-L-arginine (L-NMMA), a nonselective NOS inhibitor, in control and losartan (Ang II receptor blocker)-treated rats and rats administered S-methyl-L-thiocitrulline (SMTC), a NOS-1 inhibitor. Effects of SMTC on oxygen consumption were also examined in freshly harvested proximal tubules. Results L-NMMA and high-dose SMTC decreased RBF, but L-NMMA + losartan and low-dose SMTC did not. Qo 2 /T na increased in both L-NMMA groups. Both low- and high-dose SMTC also increased Qo 2 /T na . SMTC increased Qo 2 in proximal tubules in vitro at presumed lower levels of vectorial NaCl transport. Results suggest this effect was not mediated by influences on sodium transport alone. Conclusion Nonselective NOS inhibition increases the oxygen costs of kidney function independent of Ang II. Kidney NOS-1 is responsible for these in vivo and in vitro effects. In vitro observations suggest that NOS-1 acts in part via effects on basal metabolism and mitochondrial function.
- Published
- 2005
34. Early diabetes as a model for testing the regulation of juxtaglomerular NOS I
- Author
-
Aihua Deng, John S. Hammes, Francis B. Gabbai, Norikuni Komine, Scott C. Thomson, and Roland C. Blantz
- Subjects
Male ,medicine.medical_specialty ,Indazoles ,Physiology ,Renal function ,Nitric Oxide Synthase Type I ,Nitric Oxide ,Renal Circulation ,Nitric oxide ,chemistry.chemical_compound ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Diabetic Nephropathies ,Enzyme Inhibitors ,Rats, Wistar ,Tubuloglomerular feedback ,Feedback, Physiological ,Kidney ,omega-N-Methylarginine ,biology ,urogenital system ,Juxtaglomerular apparatus ,medicine.disease ,Juxtaglomerular Apparatus ,Rats ,Nitric oxide synthase ,medicine.anatomical_structure ,Endocrinology ,chemistry ,biology.protein ,Macula densa ,Nitric Oxide Synthase ,Glomerular Filtration Rate - Abstract
Dysregulation of kidney nitric oxide synthase (NOS) I may alter renal hemodynamics in diabetes. Four types of studies were performed in anesthetized 1- to 2-wk-streptozotocin diabetic rats. 1) Glomerular filtration rate (GFR) was measured before and during NOS I blockade. Subsequent addition of nonspecific NOS blocker tested for residual NO from other isoforms. Acute systemic NOS I blockade reduced GFR only in diabetics. Nonspecific NOS blockade had no additional effect on NOS I-blocked diabetics. 2) Renal blood flow (RBF) was monitored for evidence that tubuloglomerular feedback (TGF) resets during 1 h of continuous activation with benzolamide. NOS I blockade was added to test for the role of NOS I in TGF resetting. During 1 h of TGF activation in controls, RBF initially declined and then returned to baseline. In diabetic and NOS I-blocked rats, RBF declined and remained low. 3) The ability of NOS I blockade to increase the homeostatic efficiency of TGF in diabetes was tested by micropuncture in free-flowing nephrons. The addition of NOS I blocker to the tubular fluid increased TGF efficiency in control and diabetic rats. 4) The influence of distal salt delivery on local NOS I activity was tested by micropuncture. Henle's loop was perfused at varying rates with NOS I blocker while single-nephron GFR (SNGFR) from the late proximal tubule was measured. In controls, NOS I blockade mainly reduced SNGFR when flow through Henle's loop was high. In diabetics, NOS I blockade reduced SNGFR independently of flow through Henle's loop. In conclusion, normally, salt delivered to the macula densa (MD) exerts immediate control over MD NOS I activity. In diabetes, there is ongoing overactivity of NOS I that is not regulated by MD salt.
- Published
- 2004
35. Increased Expression of Ornithine Decarboxylase in Distal Tubules of Early Diabetic Rat Kidneys
- Author
-
Jose M. Valdivielso, Scott C. Thomson, Mark Lortie, Karen A. Munger, Aihua Deng, Joseph Satriano, and Roland C. Blantz
- Subjects
medicine.medical_specialty ,Renal Hypertrophy ,Endocrinology, Diabetes and Metabolism ,Cell cycle ,Biology ,medicine.disease ,Muscle hypertrophy ,Ornithine decarboxylase ,chemistry.chemical_compound ,Paracrine signalling ,Endocrinology ,chemistry ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Polyamine ,Glomerular hyperfiltration - Abstract
Polyamines are small biogenic molecules that are essential for cell cycle entry and progression and proliferation. They can also contribute to hypertrophy. The activity of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, increases in the early diabetic kidney to enable renal hypertrophy. Inhibition of ODC in early diabetes attenuates diabetic renal hypertrophy and glomerular hyperfiltration. The current studies examine the temporal profile of renal ODC protein expression and localization, intrarenal polyamine levels, and sites of proliferation in kidneys of rats during the first 7 days of streptozotocin diabetes. ODC mRNA and protein content were increased in diabetic kidneys. High-performance liquid chromatography analysis showed increased intrarenal polyamine concentrations peaking after 24 h of diabetes. A subsequent increase in the number of proliferating proximal tubular cells was detected by in vivo 5-bromodeoxyuridine (BrdU) incorporation on day 3. Surprisingly, immunohistochemical studies revealed that increased ODC protein was apparent only in distal nephrons, whereas the main site of diabetic kidney hypertrophy is the proximal tubule. These findings raise the possibility that polyamines produced in the distal nephron may mediate the early diabetic kidney growth of the proximal tubules via a paracrine mechanism.
- Published
- 2003
36. Glomerular Hyperfiltration and the Salt Paradox in Early Type 1 Diabetes Mellitus
- Author
-
Roland C. Blantz, Volker Vallon, and Scott C. Thomson
- Subjects
medicine.medical_specialty ,Time Factors ,Monosaccharide Transport Proteins ,Urology ,Renal function ,Disease ,Sodium Chloride ,Ornithine Decarboxylase ,Absorption ,Kidney Tubules, Proximal ,Diabetic nephropathy ,Diabetes mellitus ,Internal medicine ,Polyamines ,medicine ,Animals ,Humans ,urogenital system ,business.industry ,Reabsorption ,Nephrons ,General Medicine ,medicine.disease ,Diet ,Diabetes Mellitus, Type 1 ,Endocrinology ,Nephrology ,Renal physiology ,business ,Glomerular hyperfiltration ,Glomerular Filtration Rate ,Kidney disease - Abstract
Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review proposes a "tubulo-centric" view of glomerular function in early type I diabetes mellitus. The following are particularly discussed (1) the primary role of an increase in reabsorption by the proximal tubule in early glomerular hyperfiltration, (2) the role of sodium-glucose cotransport and tubular growth under these conditions, and (3) the primary role of reabsorption by the proximal tubule for the paradoxical relationship between dietary salt and glomerular filtration rate. Finally, an outline is presented of potential therapeutic implications for the prevention of diabetic kidney disease.
- Published
- 2003
37. Salt-Sensitivity of Proximal Reabsorption Alters Macula Densa Salt and Explains the Paradoxical Effect of Dietary Salt on Glomerular Filtration Rate in Diabetes Mellitus
- Author
-
Aihua Deng, Scott C. Thomson, Volker Vallon, Dan-Yang Huang, Roland C. Blantz, and Kerstin Richter
- Subjects
Male ,medicine.medical_specialty ,Sodium ,Kidney Glomerulus ,Renal function ,chemistry.chemical_element ,Sodium Chloride ,Absorption ,Diabetes Mellitus, Experimental ,Feedback ,Kidney Tubules, Proximal ,Rats, Sprague-Dawley ,Reference Values ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Kidney Tubules, Distal ,reproductive and urinary physiology ,Tubuloglomerular feedback ,urogenital system ,Chemistry ,Reabsorption ,Biological Transport ,Nephrons ,General Medicine ,Diet, Sodium-Restricted ,medicine.disease ,Streptozotocin ,Diet ,Rats ,Endocrinology ,medicine.anatomical_structure ,Nephrology ,Renal physiology ,Macula densa ,Glomerular Filtration Rate ,medicine.drug - Abstract
GFR varies inversely with dietary NaCl in patients with early type I diabetes and in streptozotocin (STZ)-diabetic rats. To explain this paradox within the laws of physiology, it was hypothesized that it results from heightened sensitivity of the diabetic proximal tubule to dietary salt because changes in proximal reabsorption (Jprox) elicit reciprocal adjustments in GFR through the normal actions of tubuloglomerular feedback (TGF). Micropuncture was done in rats after 5 wk of moderately hyperglycemic STZ-diabetes and 1 wk of different NaCl diets. First, single-nephron GFR (SNGFR) and early distal tubular Na(+), Cl(-) and K(+) concentration (representing the TGF signal) were measured by collecting from early distal nephrons. In nondiabetics, dietary salt did not affect SNGFR or the TGF signal. In diabetics, the TGF signal varied directly with dietary salt while SNGFR varied inversely with dietary salt. Next, Jprox was measured by collecting from late proximal tubules. To control for different SNGFR, SNGFR was manipulated by perfusing Henle's loop to alter TGF activity. Controlling for SNGFR, dietary salt did not affect Jprox in nondiabetics but exerted a major inverse impact on Jprox in diabetics. In conclusion, normal rats acclimate to dietary NaCl by primarily adjusting transport downstream of the macula densa. In contrast, diabetes renders reabsorption in the proximal tubule sensitive to dietary NaCl with subsequent effects on the TGF signal. This explains the paradoxical effect of dietary NaCl on GFR in early diabetes.
- Published
- 2002
38. Vasodilatory N-Methyl-D-Aspartate Receptors Are Constitutively Expressed in Rat Kidney
- Author
-
Roland C. Blantz, Jose M. Valdivielso, Aihua Deng, Scott C. Thomson, and Karen A. Munger
- Subjects
Male ,medicine.medical_specialty ,DNA, Complementary ,Kidney Cortex ,Glycine ,Renal function ,Vasodilation ,Biology ,Kynurenic Acid ,Receptors, N-Methyl-D-Aspartate ,Renal Circulation ,Glycine binding ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Analysis of Variance ,Kidney ,Reverse Transcriptase Polymerase Chain Reaction ,Calcium channel ,Hemodynamics ,General Medicine ,Immunohistochemistry ,Rats ,Endocrinology ,medicine.anatomical_structure ,Nephrology ,Renal blood flow ,NMDA receptor ,Dizocilpine Maleate ,medicine.symptom ,Vasoconstriction ,Glomerular Filtration Rate - Abstract
N-methyl-D-aspartate receptor (NMDA-R) is an amino acid receptor and membrane calcium channel. NMDA-R is activated by binding of coagonists, L-glutamine and L-glycine. In the brain, calcium entry via NMDA-R activates type I nitric oxide synthase (NOS I). The kidney also contains NOS I and vasodilates in response to L-glycine. In this study, NMDA-R mRNA was demonstrated in rat kidney cortex by reverse transcriptase-PCR and cDNA sequencing. NMDA-R protein was demonstrated in kidney cortex by immunoblotting. To study the functional role of renal NMDA-R, renal hemodynamic effects of NMDA-R inhibition were assessed in rats using a blocker of the NMDA calcium channel (75 mg/kg MK-801 intraperitoneally) or an inhibitor of glycine binding to NMDA-R (30 mg/kg 5,7-dichlorokynurenic acid intraperitoneally). Renal blood flow was measured by perivascular pulse Doppler. GFR was measured by 3H-inulin clearance. Measurements were made before and during glycine infusion. Both NMDA-R antagonists caused renal vasoconstriction and attenuated the renal vasodilatory response to glycine infusion. These effects were not mediated by the renal nerves. The glycine response was not inhibited by aortic snare used to mimic the effects of NMDA-R inhibitors on basal renal blood flow. NMDA-R are expressed in kidney cortex, where they exert a tonic vasodilatory influence and may account for the vasodilatory response to glycine infusion.
- Published
- 2002
39. Glomerulotubular balance, dietary protein, and the renal response to glycine in diabetic rats
- Author
-
Aihua Deng, Francis B. Gabbai, Scott C. Thomson, Larry A. Slomowitz, and John S. Hammes
- Subjects
Male ,medicine.medical_specialty ,Physiology ,Urinary system ,Kidney Glomerulus ,Glycine ,Renal function ,urologic and male genital diseases ,Diabetes Mellitus, Experimental ,Physiology (medical) ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Diabetic Nephropathies ,Rats, Wistar ,Tubuloglomerular feedback ,Kidney ,urogenital system ,Reabsorption ,Chemistry ,medicine.disease ,Rats ,Renal glucose reabsorption ,Kidney Tubules ,medicine.anatomical_structure ,Endocrinology ,Renal physiology ,Loop of Henle ,Dietary Proteins ,Glomerular Filtration Rate - Abstract
The glomerular filtration rate (GFR) normally increases during glycine infusion, which is a test of “renal reserve.” Renal reserve is absent in diabetes mellitus. GFR increases after protein feeding because of increased tubular reabsorption, which reduces the signal for tubuloglomerular feedback (TGF). Dietary protein restriction normalizes some aspects of glomerular function in diabetes. Renal micropuncture was performed in rats 4–5 wk after diabetes was induced by streptozotocin to determine whether renal reserve is lost as a result of altered tubular function and activation of TGF, whether 10 days of dietary protein restriction could restore renal reserve, and whether this results from effects of glycine on the tubule. TGF activation was determined by locating single-nephron GFR (SNGFR) in the early distal tubule along the TGF curve. The TGF signal was determined from the ionic content of the early distal tubule. In nondiabetic rats, SNGFR in the early distal tubule increased during glycine infusion because of primary vasodilation augmented by increased tubular reabsorption, which stabilized the TGF signal. In diabetic rats, glycine reduced reabsorption, thereby activating TGF, which was largely responsible for the lack of renal reserve. In protein-restricted diabetic rats, the tubular response to glycine remained abnormal, but renal reserve was restored by a vascular mechanism. Glycine affects GFR directly and via the tubule. In diabetes, reduced tubular reabsorption dominates. In low-protein diabetes, the vascular effect is enhanced and overrides the effect of reduced tubular reabsorption.
- Published
- 2002
40. The complex role of nitric oxide in the regulation of glomerular ultrafiltration
- Author
-
Roland C. Blantz, Mark Lortie, Scott C. Thomson, Aihua Deng, Volker Vallon, Francis B. Gabbai, and Karen A. Munger
- Subjects
medicine.medical_specialty ,Renal glomerulus ,receptor ,Kidney Glomerulus ,Nitric Oxide ,hemodynamics ,Nitric oxide ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Tubuloglomerular feedback ,tubuloglomerular feedback ,Kidney ,biology ,nitric oxide synthase ,urogenital system ,Nitric oxide synthase ,Kidney Tubules ,medicine.anatomical_structure ,Endocrinology ,NMDA ,chemistry ,Nephrology ,Renal blood flow ,Renal physiology ,biology.protein ,Macula densa ,Glomerular Filtration Rate - Abstract
The complex role of nitric oxide in the regulation of glomerular ultrafiltration. Nitric oxide is an important neurohumoral modulator of glomerular ultrafiltration and renal hemodynamics. Multiple nitric oxide synthase (NOS) isoforms are present within the kidney. However, it is difficult to discern which NOS is most active from prior studies using non-selective NOS blockers. It is recently apparent that NOS activity is important to the activity of tubuloglomerular feedback (TGF) systems, systems that relate tubular reabsorption to the regulation of glomerular ultrafiltration. Neuronal (nNOS) or brain NOS (bNOS; NOS I) is present within the macula densa, the sensing element of TGF systems. Inhibition of NOS activity and specifically bNOS enhances TGF activity. The TGF system also adapts temporally and these events appear to be dependent upon up-regulation of activity of bNOS within the kidney. Temporal adaptation occurs within one to three hours whereby activation of TGF is followed by a gradual return of the glomerular filtration rate (GFR) and renal blood flow toward normal levels. After 24 hours of benzolamide treatment and withdrawal of this agent, glomerular filtration actually increases to supranormal levels and this is prevented by inhibition of bNOS activity. Factors regulating bNOS activity have not been fully clarified. We have recently observed N-methyl-d-aspartate (NMDA) receptors within the kidney that, when inhibited, result in major reductions in renal blood flow and GFR, suggesting an important role for the NMDA receptor in regulation of renal hemodynamics. Future studies will determine whether NMDA receptor is also an important regulator of bNOS activity and the TGF system.
- Published
- 2002
41. Adenosine and purinergic mediators of tubuloglomerular feedback
- Author
-
Scott C. Thomson
- Subjects
medicine.medical_specialty ,Adenosine ,Adenine Nucleotides ,Chemistry ,Kidney Glomerulus ,Purinergic receptor ,Models, Biological ,Feedback ,Kidney Tubules ,Endocrinology ,Purines ,Nephrology ,Adenine nucleotide ,Internal medicine ,Renin–angiotensin system ,Internal Medicine ,medicine ,Animals ,Humans ,Neuroscience ,medicine.drug ,Tubuloglomerular feedback - Abstract
This review will focus on the role of adenosine and adenine nucleotides as potential mediators of the tubuloglomerular feedback response. The effects of these substances on tubular transport, renin release, and long-term adaptations of tubuloglomerular feedback are worthy of discussion, but will not be considered here.
- Published
- 2002
42. What makes SGLT2 inhibition so effective in lowering blood glucose in diabetes? (689.5)
- Author
-
Michael Rose, Takahiro Masuda, Maria Gerasimova, Timo Rieg, Scott C. Thomson, Volker Vallon, Eric Mayoux, and Hermann Koepsell
- Subjects
endocrine system ,medicine.medical_specialty ,urogenital system ,Chemistry ,digestive, oral, and skin physiology ,medicine.disease ,Biochemistry ,Sodium Glucose Cotransporters ,Endocrinology ,Diabetes mellitus ,Internal medicine ,Knockout mouse ,Genetics ,medicine ,Molecular Biology ,hormones, hormone substitutes, and hormone antagonists ,Biotechnology - Abstract
Studies in knockout mice indicated that, in euglycemia, the sodium glucose cotransporters SGLT2 and SGLT1 reabsorb 97 and 3% of filtered glucose, respectively. The SGLT1 contribution is enhanced to...
- Published
- 2014
43. Novel role of HIF‐1alpha in tubular Na transport in the remnant kidney (860.7)
- Author
-
Prabhleen Singh, Koji Ayoyama, Hai Pham, and Scott C. Thomson
- Subjects
medicine.medical_specialty ,urogenital system ,Remnant kidney ,Reabsorption ,HIF-1alpha ,chemistry.chemical_element ,Subtotal nephrectomy ,Hypoxia (medical) ,Biochemistry ,Oxygen ,nervous system diseases ,surgical procedures, operative ,Endocrinology ,nervous system ,chemistry ,Internal medicine ,Genetics ,medicine ,medicine.symptom ,therapeutics ,Molecular Biology ,Biotechnology - Abstract
Remnant nephrons after subtotal nephrectomy (STN) show significant hyperfiltration. We have also shown increased oxygen consumption for tubular Na reabsorption in STN leading to hypoxia. We hypothe...
- Published
- 2014
44. Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes
- Author
-
Blantz Roland, Volker Vallon, Aihua Deng, Dingjiu Bao, Scott C. Thomson, and Joseph Satriano
- Subjects
Kidney ,medicine.medical_specialty ,urogenital system ,Chemistry ,Renal function ,General Medicine ,medicine.disease ,Muscle hypertrophy ,Ornithine decarboxylase ,medicine.anatomical_structure ,Endocrinology ,Ornithine Decarboxylase Inhibitor ,Diabetes mellitus ,Internal medicine ,medicine ,Glomerular hyperfiltration ,Tubuloglomerular feedback - Abstract
In early diabetes, the kidney grows and the glomerular filtration rate (GFR) increases. This growth is linked to ornithine decarboxylase (ODC). The study of hyperfiltration has focused on microvascular abnormalities, but hyperfiltration may actually result from a prior increase in capacity for proximal reabsorption which reduces the signal for tubuloglomerular feedback (TGF). Experiments were performed in Wistar rats after 1 week of streptozotocin diabetes. Kidney weight, ODC activity, and GFR were correlated in diabetic and control rats given difluoromethylornithine (DFMO; Marion Merrell Dow, Cincinnati, Ohio, USA) to inhibit ODC. We assessed proximal reabsorption by micropuncture, using TGF as a tool for manipulating single-nephron GFR (SNGFR), then plotting proximal reabsorption versus SNGFR. ODC activity was elevated 15-fold in diabetic kidneys and normalized by DFMO, which also attenuated hyperfiltration and hypertrophy. Micropuncture data revealed an overall increase in proximal reabsorption in diabetic rats too great to be accounted for by glomerulotubular balance. DFMO prevented the overall increase in proximal reabsorption. These data confirm that ODC is required for the full effect of diabetes on kidney size and proximal reabsorption in early streptozotocin diabetes and are consistent with the hypothesis that diabetic hyperfiltration results from normal physiologic actions of TGF operating in a larger kidney, independent of any primary malfunction of the glomerular microvasculature.
- Published
- 2001
45. A New Role for Charge of the Glomerular Capillary Membrane
- Author
-
Roland C. Blantz and Scott C. Thomson
- Subjects
Physics ,One half ,Membrane ,Nephrology ,Chemical physics ,Coulomb ,Charge (physics) ,General Medicine ,Glomerular capillary - Abstract
Things move when acted on by forces. In body fluids and at tissue-fluid interfaces, Coulomb forces hold oppositely charged molecules in close proximity to one another. When one half of a charge couple is more susceptible than the other to some external driving force, imposing that driving force will
- Published
- 2010
46. Salt sensitivity of tubuloglomerular feedback in the early remnant kidney
- Author
-
Prabhleen Singh and Scott C. Thomson
- Subjects
Male ,medicine.medical_specialty ,Physiology ,medicine.medical_treatment ,Kidney Glomerulus ,Renal function ,Subtotal nephrectomy ,Blood Pressure ,Kidney ,Nephrectomy ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Sodium Chloride, Dietary ,Tubuloglomerular feedback ,Feedback, Physiological ,Analysis of Variance ,Remnant kidney ,Chemistry ,Blood Proteins ,Articles ,Capillaries ,Diet ,Rats ,Endocrinology ,medicine.anatomical_structure ,Kidney Tubules ,Salt sensitivity ,Salt balance ,Glomerular Filtration Rate - Abstract
We previously reported internephron heterogeneity in the tubuloglomerular feedback (TGF) response 1 wk after subtotal nephrectomy (STN), with 50% of STN nephrons exhibiting anomalous TGF (Singh P, Deng A, Blantz RC, Thomson SC. Am J Physiol Renal Physiol 296: F1158–F1165, 2009). Presently, we tested the theory that anomalous TGF is an adaptation of the STN kidney to facilitate increased distal delivery when NaCl balance forces the per-nephron NaCl excretion to high levels. To this end, the effect of dietary NaCl on the TGF response was tested by micropuncture in STN and sham-operated Wistar rats. An NaCl-deficient (LS) or high-salt NaCl diet (HS; 1% NaCl in drinking water) was started on day 0 after STN or sham surgery. Micropuncture followed 8 days later with measurements of single-nephron GFR (SNGFR), proximal reabsorption, and tubular stop-flow pressure (PSF) obtained at both extremes of TGF activation, while TGF was manipulated by microperfusing Henle's loop (LOH) from the late proximal tubule. Activating TGF caused SNGFR to decline by similar amounts in Sham-LS, Sham-HS and STN-LS [ΔSNGFR (nl/min) = −16 ± 2, −11 ± 3, −11 ± 2; P = not significant by Tukey]. Activating TGF in STN-HS actually increased SNGFR by 5 ± 2 nl/min ( P < 0.0005 vs. each other group by Tukey). HS had no effect on the PSFresponse to LOH perfusion in sham [ΔPSF(mmHg) = −9.6 ± 1.1 vs. −9.8 ± 1.0] but eliminated the PSFresponse in STN (+0.3 ± 0.9 vs. −5.7 ± 1.0, P = 0.0002). An HS diet leads to anomalous TGF in the early remnant kidney, which facilitates NaCl and fluid delivery to the distal nephron.
- Published
- 2013
47. Temporal adjustment of the juxtaglomerular apparatus during sustained inhibition of proximal reabsorption
- Author
-
Magdalena Bostanjoglo, Dingjiu Bao, Roland C. Blantz, Orjan W. Peterson, Sebastian Bachmann, Doron Schwartz, Carolyn A. Ecelbarger, and Scott C. Thomson
- Subjects
Male ,medicine.medical_specialty ,Diuresis ,Nitric Oxide Synthase Type I ,Nephron ,Sodium Chloride ,Absorption ,Benzolamide ,Kidney Tubules, Proximal ,Internal medicine ,medicine ,Loop of Henle ,Animals ,Rats, Wistar ,Kidney Tubules, Distal ,Tubuloglomerular feedback ,biology ,urogenital system ,Chemistry ,General Medicine ,Juxtaglomerular apparatus ,Juxtaglomerular Apparatus ,Rats ,Nitric oxide synthase ,Endocrinology ,medicine.anatomical_structure ,Commentary ,biology.protein ,Macula densa ,Nitric Oxide Synthase ,Glomerular hyperfiltration ,Glomerular Filtration Rate - Abstract
Tubuloglomerular feedback (TGF) stabilizes nephron function by causing changes in single-nephron GFR (SNGFR) to compensate for changes in late proximal flow (VLP). TGF responds within seconds and reacts over a narrow range of VLP that surrounds normal VLP. To accommodate sustained increases in VLP, TGF must reset around the new flow. We studied TGF resetting by inhibiting proximal reabsorption with benzolamide (BNZ; administered repeatedly over a 24-hour period) in Wistar-Froemter rats. BNZ acutely activates TGF, thereby reducing SNGFR. Micropuncture was performed 6-10 hours after the fourth BNZ dose, when diuresis had subsided. BNZ caused glomerular hyperfiltration, which was prevented with inhibitors of macula densa nitric oxide synthase (NOS). Because of hyperfiltration, BNZ increased VLP and distal flow, but did not affect the basal TGF stimulus (early distal salt concentration). BNZ slightly blunted normalized maximum TGF response and the basal state of TGF activation. BNZ sensitized SNGFR to reduction by S-methyl-thiocitrulline (SMTC) and caused the maximum TGF response to be strengthened by SMTC. Sensitization to type I NOS (NOS-I) blockers correlated with increased macula densa NOS-I immunoreactivity. Tubular transport measurements confirmed that BNZ affected TGF within the juxtaglomerular apparatus. During reduced proximal reabsorption, TGF resets to accommodate increased flow and SNGFR through a mechanism involving macula densa NOS.
- Published
- 1999
48. Converting Enzyme Inhibition and the Glomerular Hemodynamic Response to Glycine in Diabetic Rats
- Author
-
Orjan W. Peterson, Scott C. Thomson, and Larry A. Slomowitz
- Subjects
Male ,medicine.medical_specialty ,Kidney Glomerulus ,Glycine ,Renal function ,Angiotensin-Converting Enzyme Inhibitors ,Nephron ,urologic and male genital diseases ,Diabetes Mellitus, Experimental ,Renal Circulation ,Enalapril ,Diabetes mellitus ,Internal medicine ,Pressure ,medicine ,Animals ,Humans ,Rats, Wistar ,Renal circulation ,urogenital system ,business.industry ,Nephrons ,General Medicine ,medicine.disease ,Capillaries ,Rats ,medicine.anatomical_structure ,Endocrinology ,Nephrology ,ACE inhibitor ,business ,Glomerular hyperfiltration ,Glomerular Filtration Rate ,medicine.drug - Abstract
GFR normally increases during glycine infusion. This response is absent in humans and rats with established diabetes mellitus. In diabetic patients, angiotensin-converting enzyme inhibition (ACEI) restores the effect of glycine on GFR. To ascertain the glomerular hemodynamic basis for this effect of ACEI, micropuncture studies were performed in male Wistar-Froemter rats after 5 to 6 wk of insulin-treated streptozotocin diabetes. The determinants of single-nephron GFR (SNGFR) were assessed in each rat before and during glycine infusion. Studies were performed in diabetics, diabetics after 5 d of ACEI (enalapril in the drinking water), and weight-matched controls. Diabetic rats manifest renal hypertrophy and glomerular hyperfiltration but not glomerular capillary hypertension. ACEI reduced glomerular capillary pressure, increased glomerular ultrafiltration coefficient, and did not mitigate hyperfiltration. In controls, glycine increased SNGFR by 30% due to increased nephron plasma flow. In diabetics, glycine had no effect on any determinant of SNGFR. In ACEI-treated diabetics, the SNGFR response to glycine was indistinguishable from nondiabetics, but the effect of glycine was mediated by greater ultrafiltration pressure rather than by greater plasma flow. These findings demonstrate that: (1) The absent response to glycine in established diabetes does not indicate that renal functional reserve is exhausted by hyperfiltration; and (2) ACEI restores the GFR response to glycine in established diabetes, but this response is mediated by increased ultrafiltration pressure rather than by increased nephron plasma flow.
- Published
- 1999
49. Contents Vol. 30, 2007
- Author
-
Astrid Starke, Johannes Donauer, Michal Mysliwiec, Rudolf P. Wüthrich, Brigitta Rumberger, Patricia R. Wahl, Jens Timmer, Maciej Szmitkowski, Rabia Alkan, Krystyna Pawlak, Romana Rysava, Jochen Wilpert, Ying Waeckerle-Men, Clemens Kreutz, Hanna Bachórzewska-Gajewska, Volker Vallon, Scott C. Thomson, Stephan R. Orth, Bernhard Banas, Sławomir Dobrzycki, S. Lawnicki, Peter Gerke, Ramazan Yigitoglu, Kerstin Amann, Adrian Covic, Oliver Vonend, Mehmet Kanbay, Roland C. Blantz, Rolf Rohrbach, Gerd Walz, Eberhard Ritz, Günter Schiele, Jacek S. Malyszko, Ali Akcay, Cynthia M. Miracle, J.S. Malyszko, Feridun Karakurt, Bunyamin Isik, E. Sitniewska, Faruk Turgut, and Timo Rieg
- Subjects
Nephrology ,General Medicine ,Cardiology and Cardiovascular Medicine - Published
- 2007
50. Vascular contributions to pathogenesis of acute renal failure
- Author
-
Ponnal Nambi, Wilhelm Kriz, Michael S. Goligorsky, Scott C. Thomson, Roland C. Blantz, and Lise Bankir
- Subjects
medicine.medical_specialty ,Ischemia ,Renal function ,Kidney ,Nitric Oxide ,urologic and male genital diseases ,Critical Care and Intensive Care Medicine ,Pathogenesis ,Animal model ,Internal medicine ,medicine ,Animals ,Humans ,Renal tubule ,business.industry ,Acute kidney injury ,General Medicine ,Acute Kidney Injury ,Kidney Tubular Necrosis, Acute ,Prognosis ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,Nephrology ,Cardiology ,Endothelium, Vascular ,business ,Kidney disease - Abstract
(1998). Vascular contributions to pathogenesis of acute renal failure. Renal Failure: Vol. 20, No. 5, pp. 663-677.
- Published
- 1998
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.