Acute In Vivo Analysis of ATP Release in Rat Kidneys in Response to Changes of Renal Perfusion Pressure

Palygin, Oleg; Evans, Louise; Cowley, Allen W.; Staruschenko, Alexander

doi:10.1161/jaha.117.006658

Cited by 22 publications

(24 citation statements)

References 64 publications

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“…), which mediates ATP release in the distal tubule (Palygin et al . ), impairs the PN response in mice.…”

Section: Discussionmentioning

confidence: 94%

“…Another candidate is ATP, which is normally released in response to increased renal perfusion pressure (Palygin et al . ) and inhibits tubular sodium transport through ENaC (Menzies et al . ).…”

Section: Discussionmentioning

confidence: 99%

“…NO, discussed above, is an attractive potential candidate. Another candidate is ATP, which is normally released in response to increased renal perfusion pressure (Palygin et al 2017) and inhibits tubular sodium transport through ENaC (Menzies et al 2015). Notably, genetic deletion of connexin 30 (Sipos et al 2009), which mediates ATP release in the distal tubule (Palygin et al 2017), impairs the PN response in mice.…”

Section: Discussionmentioning

confidence: 99%

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Impaired pressure natriuresis and non‐dipping blood pressure in rats with early type 1 diabetes mellitus

Culshaw

Costello

Binnie

et al. 2018

The Journal of Physiology

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Key points Type 1 diabetes mellitus increases cardiovascular risk; hypertension amplifies this risk, while pressure natriuresis regulates long‐term blood pressure.We induced type 1 diabetes in rats by streptozotocin injection and demonstrated a substantial impairment of pressure natriuresis: acute increases in blood pressure did not increase renal medullary blood flow, tubular sodium reabsorption was not downregulated, and proximal tubule sodium reabsorption, measured by lithium clearance, was unaffected.Insulin reduced blood glucose in diabetic rats, and rescued the pressure natriuresis response without influencing lithium clearance, but did not restore medullary blood flow.Radiotelemetry showed that diastolic blood pressure was increased in diabetic rats, and its diurnal variation was reduced.Increases in medullary blood flow and decreases in distal tubule sodium reabsorption that offset acute rises in BP are impaired in early type 1 diabetes, and this impairment could be a target for preventing hypertension in type 1 diabetes. AbstractType 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague‐Dawley rats were injected with streptozotocin (30–45 mg/kg) or citrate vehicle. After 3 weeks, pressure natriuresis was induced by serial arterial ligation. In non‐diabetic controls, this increased fractional excretion of sodium from ∼1% to ∼25% of the filtered load (P < 0.01); in T1DM rats, the response was significantly blunted, peaking at only ∼3% (P < 0.01). Mechanistically, normal lithium clearance suggested that distal tubule sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. Radiotelemetry showed that T1DM did not affect systolic BP, but mean diastolic BP was ∼5 mmHg higher than in non‐diabetic controls (P < 0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.

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“…), which mediates ATP release in the distal tubule (Palygin et al . ), impairs the PN response in mice.…”

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impaired pressure natriuresis and non‐dipping blood pressure in rats with early type 1 diabetes mellitus

Culshaw

Costello

Binnie

et al. 2018

The Journal of Physiology

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“…The detailed application of the biosensor amperometry technique to assess H 2 O 2 levels in the kidney was previously described. 28,29 Briefly, animals were prepared using an anesthetic mixture of ketamine (20 mg/kg, intramuscularly) and inactin (50 mg/kg, i.p.) and placed on a temperature-controlled surgical table.…”

Section: Measurement Of H 2 O 2 Level In Vivomentioning

confidence: 99%

NOX4‐dependent regulation of ENaC in hypertension and diabetic kidney disease

et al. 2020

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NADPH oxidase 4 (NOX4) is the most abundant NOX isoform in the kidney; however, its importance for renal function has only recently emerged. The NOX4‐dependent pathway regulates many factors essential for proper sodium handling in the distal nephron. However, the functional significance of this pathway in the control of sodium reabsorption during the initiation of chronic kidney disease is not established. The goal of this study was to test Nox4‐dependent ENaC regulation in two models: SS hypertension and STZ‐induced type 1 diabetes. First, we showed that genetic ablation of Nox4 in Dahl salt‐sensitive (SS) rat attenuated a high‐salt (HS)‐induced increase in epithelial Na+ channel (ENaC) activity in the cortical collecting duct. We also found that H2O2 upregulated ENaC activity, and H2O2 production was reduced in both the renal cortex and medulla in SSNox4−/− rats fed an HS diet. Second, in the streptozotocin model of hyperglycemia‐induced renal injury ENaC activity in hyperglycemic animals was elevated in SS but not SSNox4−/− rats. NaCl cotransporter (NCC) expression was increased compared to healthy controls, while expression values between SS and SSNox4−/− groups were similar. These data emphasize a critical contribution of the NOX4‐mediated pathway in maladaptive upregulation of ENaC‐mediated sodium reabsorption in the distal nephron in the conditions of HS‐ and hyperglycemia‐induced kidney injury.

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“…Biosensors for H 2 O 2 analysis were obtained from Sarissa Biomedical Inc. and used previously to assess extracellular H 2 O 2 concentrations ex vivo and in vivo. 29…”

Section: H 2 O 2 Level Measurements With Enzymatic Biosensorsmentioning

confidence: 99%

A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease

Ilatovskaya

Blass

Palygin

et al. 2018

JASN

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107

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Loss of glomerular podocytes is an indicator of diabetic kidney disease (DKD). The damage to these cells has been attributed in part to elevated intrarenal oxidative stress. The primary source of the renal reactive oxygen species, particularly HO, is NADPH oxidase 4 (NOX4). We hypothesized that NOX4-derived HO contributes to podocyte damage in DKD elevation of podocyte calcium. We used Dahl salt-sensitive (SS) rats with a null mutation for the gene (SS) and mice with knockout of the nonselective calcium channel TRPC6 or double knockout of TRPC5 and TRPC6. We performed whole animal studies and used biosensor measurements, electron microscopy, electrophysiology, and live calcium imaging experiments to evaluate the contribution of this pathway to the physiology of the podocytes in freshly isolated glomeruli. Upon induction of type 1 diabetes with streptozotocin, SS rats exhibited significantly lower basal intracellular Ca levels in podocytes and less DKD-associated damage than SS rats did. Furthermore, the angiotensin II-elicited calcium flux was blunted in glomeruli isolated from diabetic SS rats compared with that in glomeruli from diabetic SS rats. HO stimulated TRPC-dependent calcium influx in podocytes from wild-type mice, but this influx was blunted in podocytes from 6-knockout mice and, in a similar manner, in podocytes from5/6 double-knockout mice. Finally, electron microscopy revealed that podocytes of glomeruli isolated from 6-knockout or5/6 double-knockout mice were protected from damage induced by HO to the same extent. These data reveal a novel signaling mechanism involving NOX4 and TRPC6 in podocytes that could be pharmacologically targeted to abate the development of DKD.

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Acute In Vivo Analysis of ATP Release in Rat Kidneys in Response to Changes of Renal Perfusion Pressure

Cited by 22 publications

References 64 publications

Impaired pressure natriuresis and non‐dipping blood pressure in rats with early type 1 diabetes mellitus

Impaired pressure natriuresis and non‐dipping blood pressure in rats with early type 1 diabetes mellitus

NOX4‐dependent regulation of ENaC in hypertension and diabetic kidney disease

A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease

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