KV7.1 channel blockade inhibits neonatal renal autoregulation triggered by a step decrease in arterial pressure

KV7, the voltage-gated potassium channels encoded by KCNQ genes, mediate heterogeneous vascular responses in adult rodents. Postnatal changes in the functional expression of KV7 channels have been reported in rodent saphenous arteries, but their physiological function in the neonatal renal vascular bed is unclear. Here, we report that, unlike adult pigs, only KCNQ1 (KV7.1) out of the five members of KCNQ genes was detected in neonatal pig renal microvessels. KCNQ1 is present in fetal pig kidneys as early as day 50 of gestation, and the level of expression remains the same up to postnatal day 21. Activation of the renal vascular smooth muscle cell (SMC) KV7.1 stimulated whole-cell currents, inhibited by HMR1556 (HMR), a selective KV7.1 blocker. HMR did not change the steady-state diameter of isolated renal microvessels. Similarly, intrarenal artery infusion of HMR did not alter the mean arterial pressure (MAP), renal blood flow (RBF), and renal vascular resistance (RVR) in the pigs. An approximately 20 mmHg reduction in the MAP evoked effective autoregulation of the RBF, which HMR inhibited. We conclude that 1) The expression of KCNQ isoforms in porcine renal microvessels is dependent on kidney maturation, 2) KV7.1 is functionally expressed in neonatal pig renal vascular SMCs, 3) a decrease in arterial pressure up to 20 mmHg induces renal autoregulation in neonatal pigs, and 4) SMC KV7.1 does not control basal renal vascular tone but contributes to neonatal renal autoregulation triggered by a step decrease in arterial pressure.

P0999URINARY EXCRETION OF ADENYLATE AND URIDYLATE NUCLEOTIDES IN STREPTOZOTOCIN-INDUCED DIABETIC RATS

Background and Aims Extracellular nucleotides (ATP, ADP, UTP, UDP) acting through P2-receptors regulate renal vascular tone and glomerular permeability tor albumin. Both phenomenons are dysregulated in diabetes and are conducive to development of diabetic nephropathy. The aim of study was to investigate the urinary excretion of adenylate and uridynate nucleotides and the effects of suramin, P2-receptors antagonist and non-competitive inhibitor of ectoATPase, on those parameters in streptozotocin-induced diabetic rats. Method Diabetes in Wistar rats was induced by streptozotocin injection (65 mg/kg, i.p, day 0) and suramin was injected (10 mg/kg, i.p) on day 7 and 14. Nucleotides concentration in urine collected in metabolic cages on day 21 (3-weeks diabetes) were measured using HPLC method wit UV detector. All values are expressed as mean ± SEM. Results The excretion of ATP, UTP, ADP and UDP in diabetes were increased i.e. ATP: 34.99±1.73 vs 18.56±1.59 μmol/24h (p<0.001); UTP: 0,72±0.06 vs 0.47±0,08 vs μmol/24h (p=0.03); ADP: 0,70±0.56 vs 0.28±0,04 vs μmol/24h (p=0.001); UDP: 9.08±1.28 vs 5.06±0,83 vs μmol/24h (p=0.02). UMP excretion was decreased 7.04±0.89 vs 11.36±0,621 μmol/24h (p=0.002) but AMP excretion was not affected by diabetes i.e. 0.86±0.09 vs 0.89±0.12 μmol/24h (p=0.08). Suramin administration did not affect urinary excretion of investigated nucleotides. Conclusion diabetes increases the urinary excretion of ATP, ADP, UTP and UDP and this effect is not modified by suramin. The changes in extracellular metabolism of nucleotides may affect the renal function during diabetes. This work was supported by National Science Centre Poland Grant (2016/23/B/NZ5/02632) to MJ.

Rehabilitation of patients with chronic pyelonephritis using mineral waters

Relevance. The study of alternative non-drug methods of rehabilitation therapy is an important task in the preventive direction of rehabilitation medicine. An important role in rehabilitation measures to prevent relapse of nephrolithiasis is therapy with the use of balneological therapeutic factors. The purpose of the study is to increase the effectiveness of rehabilitation therapy in patients with chronic pyelonephritis with the use of Serebryaniy klyuch mineral water. Materials and research methods. The basis of the work is the analysis of data from examination and treatment of 48 patients with chronic pyelonephritis in the phase of latent inflammation. All patients included in the study were divided into 2 groups. Patients of the 1st group (n = 23) were prescribed antibacterial, antispasmodic, herbal medicine and drinking fresh water. In addition to standard therapy, patients of the 2nd main group (n = 25) were prescribed 300350 ml of Serebryaniy klyuch mineral water 3040 minutes before meals up to 2 liters per day at a temperature of 3940 C. Results. In patients of the 2nd group in 91.4% of cases, curation of the clinical signs of the disease was noted, pathogens were eliminated in 100% of patients. At the same time, normalization of cytokine homeostasis and humoral immunity was observed, which contributed to a decrease in interstitial edema and normalization of renal vascular tone. Conclusion. The internal intake of Serebryaniy klyuch mineral water in the rehabilitation therapy of patients with chronic pyelonephritis has a positive effect on the elimination of the clinical manifestations of the disease, increases the percentage of sterile urine culture, improves the basal blood flow in the kidneys, the immune status of patients, the cytokine profile of blood serum and there by increases the duration of the full clinical and laboratory remission in this category of patients.

Renovascular BKCa channels are not activated in vivo under resting conditions and during agonist stimulation

We investigated the role of large-conductance Ca2+-activated K+ (BKCa) channels for the basal renal vascular tone in vivo. Furthermore, the possible buffering by BKCa of the vasoconstriction elicited by angiotensin II (ANG II) or norepinephrine (NE) was investigated. The possible activation of renal vascular BKCa channels by cAMP was investigated by infusing forskolin. Renal blood flow (RBF) was measured in vivo using electromagnetic flowmetry or ultrasonic Doppler. Renal preinfusion of tetraethylammonium (TEA; 3.0 μmol/min) caused a small reduction of baseline RBF, but iberiotoxin (IBT; 0.3 nmol/min) did not have any effect. Renal injection of ANG II (1–4 ng) or NE (10–40 ng) produced a transient decrease in RBF. These responses were not affected by preinfusion of TEA or IBT. Renal infusion of the BKCa opener NS-1619 (90.0 nmol/min) did not affect basal RBF or the response to NE, but it attenuated the response to ANG II. Coadministration of NS-1619 with TEA or IBT abolished this effect. Forskolin caused renal vasodilation that was not inhibited by IBT. The presence of BKCa channels in the preglomerular vessels was confirmed by immunohistochemistry. Despite their presence, there is no indication for a major role for BKCa channels in the control of basal renal tone in vivo. Furthermore, BKCa channels do not have a buffering effect on the rat renal vascular responses to ANG II and NE. The fact that NS-1619 attenuates the ANG II response indicates that the renal vascular BKCa channels can be activated under certain conditions.

Stimulation of renin release by prostaglandin E2 is mediated by EP2 and EP4 receptors in mouse kidneys

PGE2 is a potent stimulator of renin release. So far, the contribution of each of the four PGE2 receptor subtypes (EP1–EP4) in the regulation of renin release has not been characterized. Therefore, we investigated the effects PGE2 on renin secretion rates (RSR) from isolated, perfused kidneys of EP1−/−, EP2−/−, EP3−/−, EP4−/−, and wild-type mice. PGE2 concentration dependently stimulated RSR from kidneys of all four knockout strains with a threshold concentration of 1 nM in EP1−/−, EP2−/−, EP3−/−, and wild-type mice, whereas the threshold concentration was shifted to 10 nM in EP4−/− mice. Moreover, the maximum stimulation of RSR by PGE2 at 1 μM was significantly reduced in EP4−/− (12.8-fold of control) and EP2−/− (15.9-fold) compared with wild-type (20.7-fold), EP1−/− (23.8-fold), and EP3−/− (20.1-fold). In contrast, stimulation of RSR by either the loop diuretic bumetanide or the β-adrenoceptor agonist isoproterenol was similar in all strains. PGE2 exerted a dual effect on renal vascular tone, inducing vasodilatation at low concentrations (1 nmol/) and vasoconstriction at higher concentrations (100 nmol/) in kidneys of wild-type mice. In kidneys of EP2−/− as well as EP4−/− mice, vasodilatation at low PGE2 concentrations was prevented, whereas vasoconstriction at higher concentrations was augmented. In contrast, the vasodilatatory component was pronounced in kidneys of EP1 and EP3 knockout mice, whereas in both genotypes the vasoconstriction at higher PGE2 concentrations was markedly blunted. Our data provide evidence that PGE2 stimulates renin release via activation of EP2 and EP4 receptors, whereas EP1 and EP3 receptors appear to be without functional relevance in juxtaglomerular cells. In contrast, all four receptor subtypes are involved in the control of renal vascular tone, EP1 and EP3 receptors increasing, and EP2 as well as EP4 receptors, decreasing it.