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.

Effects of Renal Denervation on the Enhanced Renal Vascular Responsiveness to Angiotensin II in High-Output Heart Failure: Angiotensin II Receptor Binding Assessment and Functional Studies in Ren-2 Transgenic Hypertensive Rats

Detailed mechanism(s) of the beneficial effects of renal denervation (RDN) on the course of heart failure (HF) remain unclear. The study aimed to evaluate renal vascular responsiveness to angiotensin II (ANG II) and to characterize ANG II type 1 (AT1) and type 2 (AT2) receptors in the kidney of Ren-2 transgenic rats (TGR), a model of ANG II-dependent hypertension. HF was induced by volume overload using aorto-caval fistula (ACF). The studies were performed two weeks after RDN (three weeks after the creation of ACF), i.e., when non-denervated ACF TGR enter the decompensation phase of HF whereas those after RDN are still in the compensation phase. We found that ACF TGR showed lower renal blood flow (RBF) and its exaggerated response to intrarenal ANG II (8 ng); RDN further augmented this responsiveness. We found that all ANG II receptors in the kidney cortex were of the AT1 subtype. ANG II receptor binding characteristics in the renal cortex did not significantly differ between experimental groups, hence AT1 alterations are not responsible for renal vascular hyperresponsiveness to ANG II in ACF TGR, denervated or not. In conclusion, maintained renal AT1 receptor binding combined with elevated ANG II levels and renal vascular hyperresponsiveness to ANG II in ACF TGR influence renal hemodynamics and tubular reabsorption and lead to renal dysfunction in the high-output HF model. Since RDN did not attenuate the RBF decrease and enhanced renal vascular responsiveness to ANG II, the beneficial actions of RDN on HF-related mortality are probably not dominantly mediated by renal mechanism(s).

Angiotensin II and the Renal Hemodynamic Response to an Isolated Increased Renal Venous Pressure in Rats

Elevated central venous pressure increases renal venous pressure (RVP) which can affect kidney function. We previously demonstrated that increased RVP reduces renal blood flow (RBF), glomerular filtration rate (GFR), and renal vascular conductance (RVC). We now investigate whether the RAS and RBF autoregulation are involved in the renal hemodynamic response to increased RVP. Angiotensin II (ANG II) levels were clamped by infusion of ANG II after administration of an angiotensin-converting enzyme (ACE) inhibitor in male Lewis rats. This did not prevent the decrease in ipsilateral RBF (−1.9±0.4ml/min, p<0.05) and GFR (−0.77±0.18ml/min, p<0.05) upon increased RVP; however, it prevented the reduction in RVC entirely. Systemically, the RVP-induced decline in mean arterial pressure (MAP) was more pronounced in ANG II clamped animals vs. controls (−22.4±4.1 vs. −9.9±2.3mmHg, p<0.05), whereas the decrease in heart rate (HR) was less (−5±6bpm vs. −23±4bpm, p<0.05). In animals given vasopressin to maintain a comparable MAP after ACE inhibition (ACEi), increased RVP did not impact MAP and HR. RVC also did not change (0.018±0.008ml/minˑmmHg), and the reduction of GFR was no longer significant (−0.54±0.15ml/min). Furthermore, RBF autoregulation remained intact and was reset to a lower level when RVP was increased. In conclusion, RVP-induced renal vasoconstriction is attenuated when ANG II is clamped or inhibited. The systemic effect of increased RVP, a decrease in HR related to a mild decrease in blood pressure, is attenuated also during ANG II clamp. Last, RBF autoregulation remains intact when RVP is elevated and is reduced to lower levels of RBF. This suggests that in venous congestion, the intact RBF autoregulation could be partially responsible for the vasoconstriction.

Urinary SARS-CoV-2 RNA Is an Indicator for the Progression and Prognosis of COVID-19

Background: We aimed to analyze clinical characteristics and find potential factors to predict poor prognosis in patients with coronavirus disease 2019 (COVID-19). Methods: We analyzed the clinical characteristics and laboratory tests of COVID-19 patients and detected SARS-CoV-2 RNA in urine sediments collected from 53 COVID-19 patients enrolled in Renmin Hospital of Wuhan University from 31 January 2020 to 18 February 2020 with qRT-PCR analysis. Then, we classified those patients based on clinical conditions (severe or non-severe syndrome) and urinary SARS-CoV-2 RNA (URNA− or URNA+). Results: We found that COVID-19 patients with severe syndrome (severe patients) showed significantly higher positive rate (11 of 23, 47.8%) of urinary SARS-CoV-2 RNA than non-severe patients (4 of 30, 13.3%, p = 0.006). URNA+ patients or severe URNA+ subgroup exhibited higher prevalence of inflammation and immune discord, cardiovascular diseases, liver damage and renal dysfunction, and higher risk of death than URNA− patients. To understand the potential mechanisms underlying the viral urine shedding, we performed renal histopathological analysis on postmortems of patients with COVID-19 and found severe renal vascular endothelium lesion characterized by an increase of the expression of thrombomodulin and von Willebrand factor, markers to assess the endothelium dysfunction. We proposed a theoretical and mathematic model to depict the potential factors that determine the urine shedding of SARS-CoV-2. Conclusions: This study indicated that urinary SARS-CoV-2 RNA detected in urine specimens can be used to predict the progression and prognosis of COVID-19 severity.

Renal arteriovenous malformation and venous thrombosis: a tumour-like presentation

Renal arteriovenous malformation is a primarily congenital renal vascular abnormality. It is usually diagnosed incidentally on imaging, and the most common subtype is ‘cirsoid’, consisting of multiple, enlarged arterial feeders interconnecting with draining veins. We present a 74-year-old woman with an incidental finding of what was at first considered a hypervascularised kidney tumour but turned out to be a left intrarenal arteriovenous malformation associated with a left renal vein thrombosis. Selective endovascular embolisation was performed. The cause-consequence relationship between the arteriovenous malformation and the thrombosis is unique. To our knowledge, no such case has ever been reported.

VEGFR3 tyrosine kinase inhibition aggravates cisplatin nephrotoxicity

Expansion of renal lymphatic networks, or lymphangiogenesis (LA) is well-recognized during development, and is now being implicated in kidney diseases. Though LA is associated with multiple pathological conditions, very little is known about its role in acute kidney injury (AKI). The purpose of this study was to evaluate the role of LA in a model of cisplatin-induced nephrotoxicity. LA is predominately regulated by VEGF-C and VEGF-D, ligands that exert their function through their cognate receptor VEGFR3. We demonstrate the use of MAZ51, a selective VEGFR3 inhibitor, which caused significantly worse structural and functional kidney damage in cisplatin nephrotoxicity. Apoptotic cell death and inflammation were also increased in the MAZ51 treated animals compared to vehicle-treated animals following cisplatin administration. Notably, MAZ51 caused significant upregulation of intrarenal phospho-NF-kB, phospho-JNK, and IL-6. Cisplatin nephrotoxicity is associated with vascular congestion due to endothelial dysfunction. Using three-dimensional tissue cytometry, a novel approach to explore lymphatics in the kidney, we detected significant vascular autofluorescence attributed to erythrocytes in cisplatin alone treated animals. Interestingly, no such congestion was detected in MAZ51 treated animals. We found increased renal vascular damage in MAZ51 treated animals, whereby MAZ51 caused a modest decrease in endothelial markers Emcn and vWF, with a modest increase in VEGFR2. Our findings identify a protective role for de novo LA in cisplatin nephrotoxicity and provide a rationale for the development of therapeutic approaches targeting LA. Our studies also suggest off target effects of MAZ51 on the vasculature in the setting of cisplatin nephrotoxicity.

A study to compare hemoglobin levels and body mass index in normal and diagnosed diabetic stages of CKD patients visiting a tertiary care hospital

Chronic kidney disease (CKD) has become a worldwide community health problem in people with type, 2 diabetes obesity and long-term hyperglycemia may cause renal vascular complications. The aim of this study was to see if there was any connection between BMI, haemoglobin and CKD in DM patients. This case study was conducted in department of Medicine, Era′s Lucknow Medical College and Hospital, ERA University, Lucknow. The analysis was performed for 18 months.When compared to CKD patients, the non-CKD group's mean BMI was marginally higher. Older age, female sex, hypertension, and diet plant were all linked to the involvement of CKD in multivariable study. There was same connection between CKD and haemoglobin in this study. The negative relationship between BMI, Hb and CKD could indicate reverse causality. While a diabetic patient's BMI does not cause them to develop CKD, it is possible that CKD causes them to have a lower BMI and Hb level.

Dynamics of GRK2 in the kidney: a putative mechanism for sepsis-associated kidney injury

Renal vascular reactivity to vasoconstrictors is preserved in sepsis in opposition to what happens in the systemic circulation. We studied whether this distinct behavior was related to α1 adrenergic receptor density, G protein-coupled receptor kinase 2 (GRK2) and the putative role of nitric oxide (NO). Sepsis was induced in female mice by cecal ligation and puncture (CLP). Wild-type mice were treated with prazosin 12 hours after CLP or NOS-2 inhibitor, 30 min before and 6 and 12 hours after CLP. In vivo experiments and biochemistry assays were performed 24 hours after CLP. Sepsis decreased the systemic mean arterial pressure and the vascular reactivity to phenylephrine. Sepsis also reduced basal renal blood flow which was normalized by treatment with prazosin. Sepsis led to a substantial decreased in GRK2 level associated to an increase in α1 adrenergic receptor density in the kidney. The disappearance of renal GRK2 was prevented in NOS-2-KO mice or mice treated with 1400W. Treatment of non-septic mice with a NO donor reduced GRK2 content in the kidney. Therefore, our results show that a NO-dependent reduction in GRK2 level in the kidney leads to the maintenance of a normal α1 adrenergic receptor density, probably. The preservation of the density and/or functionality of this receptor in the kidney together with a higher vasoconstrictor tonus in sepsis lead to vasoconstriction. Thus, the increased concentration of vasoconstrictor mediators together with the preservation (and even increase) of the response to them may help to explain sepsis-induced acute kidney injury.

Clinicopathological Characteristics and Influencing Factors of Renal Vascular Lesions in Anti-neutrophil Cytoplasmic Autoantibody-Related Renal Vasculitis

The purpose of this study was to evaluate the clinicopathological features of different degrees of extraglomerular renal vascular lesions (RVLs) in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis and explore their clinical determinants. This is a retrospective study of 186 patients with ANCA-associated renal vasculitis diagnosed at the First Affiliated Hospital of Zhengzhou University from January 2014 to April 2019. The patients who met the inclusion criteria were divided into non-renal RVLs, mild RVLs, moderate RVLs, and severe RVLs. It was found that there were significant differences in serum creatinine (SCR), estimated glomerular filtration rate (eGFR), erythrocyte sedimentation rate (ESR), high-density lipoprotein (HDL), systolic blood pressure (SBP), the prevalence rate of hypertension, the proportion of normal glomeruli, and the proportion of sclerotic glomeruli and interstitial fibrosis integral. SCR and ESR are independent risk factors for RVLs. The participants were followed up for 1 year, and the progression to end-stage renal disease (ESRD) and death was defined as endpoint events. We found that the survival rate of patients without RVLs was significantly higher than that of patients with RVLs and that the RVLs were an independent risk factor for ESRD or death. Early intervention in the progression of RVLs can improve the prognosis.