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Metabolic Syndrome (MetS) affects more than 30% of the US population and unmanaged can lead to cardiovascular disease and type II diabetes mellitus. MetS is a cluster of conditions, which include elevated arterial pressure, poor glucose tolerance with or without insulin resistance, and abdominal obesity. Existing literature has demonstrated high cholesterol diet’s (HCD) potential to develop MetS cluster factor conditions like dyslipidemia. Our lab has previously shown that angiotensin receptor blockers (ARBs), a common therapy to treat hypertension by disrupting the renin-angiotensin-aldosterone system (RAAS), attenuate cluster factor conditions of MetS. However, the efficacy of ARBs during the consumption of a HCD remains unclear. Otsuka Long Evan Tokushima Fatty (OLETF) rats (a MetS model) were fed an HCD and at presentation of elevated arterial pressure, they were treated with ARB (10 mg olmesartan/kg/d x 3 wks) by oral gavage. Blood pressure was monitored in real-time with surgically implanted radio telemeters. ARB reduced systolic blood pressure by 15±1mmHg (11%; p This work was supported by the National Institutes of Health NCMHD 9T37MD001480 and National Institutes of Health, National Center on Minority Health and Health Disparities. E.E.J was supported by NIH GRISE BIO-STeP. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardiovascular disease (CVD) is the leading cause of death among individuals with Type II diabetes (T2D) with approximately 30 million people afflicted within the United States. Diabetic cardiomyopathy is defined as cardiovascular dysfunction induced by diabetic complications such as sustained hyperglycemia and insulin resistance. During insulin resistance the heart undergoes a metabolic shift in which fatty acids (FA) accounts for about 99% of the ATP production. Some major consequences of a metabolic shift with impaired glucose tolerance can cause an increase in reactive oxygen species (ROS), lipotoxicity, mitochondrial dysfunction, ultimately leading to cardiovascular dysfunction. We have previously shown thyroid hormones (THs) increase GLUT4 translocation in cardiac tissue, indicating the potential to improve the impaired glucose metabolism in the heart. THs have also been shown to improve oxidative injury and increase antioxidant defense systems yet contradicting data exists demonstrating THs induce oxidative stress. Thus, the effects of THs on redox biology and oxidative stress are incongruent and warrant further investigation. Insulin resistant, Otsuka Long Evans Tokushima Fatty (OLETF) rats were used to assess the effects of exogenous thyroxine (T4) on oxidative damage and antioxidant defense in cardiac tissue. Rats were assigned to four groups: 1) lean, Long Evans Tokushima Otsuka (LETO; n=6), 2) LETO + T4 (8 μg/100g BM/d × 5 wks; n=7), 3) untreated OLETF (n=6), and 4) OLETF + T4 (n=7). T4 increased NADPH oxidase (NOX) NOX2 mRNA in both treated LETO (2.04 ± 0.6) and OLETF (2.02 ± 0.6) compared to LETO control (1 ± 0.2). T4 further increased NOX4 mRNA in OLETF by 78% compared to untreated OLETF. In addition, T4 increased Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) protein expression in OLETF by 45% compared to untreated OLETF. These data suggest that the potential for an oxidizing environment in the insulin resistant OLETF rat is increased and T4 has the cardioprotective potential to increase Nrf2-mediated antioxidant defense mechanisms. APS Porter Fellowship and American Heart Association grant # 946746. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002–2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC. NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.

Klotho interacts with various membrane proteins such as receptors for transforming growth factor-β (TGF-β) and insulin-like growth factor (IGF). Renal expression of klotho is diminished in polycystic kidney disease (PKD). In the present study, the effects of klotho supplementation on PKD were assessed. Recombinant human klotho protein (10 μg·kg−1·day−1) or a vehicle was administered daily by subcutaneous injection to 6-wk-old mice with PKD (DBA/2-pcy). Blood pressure was measured using tail-cuff methods. After 2 mo, mice were killed, and the kidneys were harvested for analysis. Exogenous klotho protein supplementation reduced kidney weight, cystic area, systolic blood pressure, renal angiotensin II levels, and 8-epi-PGF2αexcretion ( P < 0.05). Klotho protein supplementation enhanced glomerular filtration rate, renal expression of superoxide dismutase, and klotho itself ( P < 0.05). Klotho supplementation attenuated renal expressions of TGF-β and collagen type I and diminished renal abundance of Twist, phosphorylated Akt, and mammalian target of rapamycin ( P < 0.05). Pathological examination revealed that klotho decreased the fibrosis index and nuclear staining of Smad in PKD kidneys ( P < 0.05). Our data indicate that klotho protein supplementation ameliorates the renin-angiotensin system, reducing blood pressure in PKD mice. Furthermore, the present results implicate klotho supplementation in the suppression of Akt/mammalian target of rapamycin signaling, slowing cystic expansion. Finally, our findings suggest that klotho protein supplementation attenuated fibrosis at least partly by inhibiting epithelial mesenchymal transition in PKD.

We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technology and investigated blood pressure and phenotype in SHR. Blood pressure was measured by tail-cuff and telemetry methods. Histology and expression of liver X receptor α (LXRα), renin, Krüppel-like factor 5 (KLF5), and E-cadherin were evaluated in kidneys. Mesangial cells (MCs) were removed from glomeruli from three strains, and we evaluated the phenotype in vitro. SHR showed the salt-sensitive hypertension that was abolished in C3 knockout (KO) SHR. Proliferation of MCs from SHR was higher than that from Wistar-Kyoto (WKY) rats and showed a synthetic phenotype. Renal injury scores were higher in SHR than in WKY rats and C3 KO SHR. Expression of E-cadherin was lower, and expression of renin was higher in the nephrotubulus from SHR than WKY rats and C3 KO SHR. Expression of C3 α-chain protein and α-smooth muscle actin protein was significantly higher in renal medulla from SHR than from WKY rats. Expression of angiotensinogen, LXRα, renin, and KLF5 mRNA was increased in kidney from SHR compared with C3 KO SHR. Intrarenal angiotensin II levels were significantly higher in kidney from SHR than WKY rats and C3 KO SHR. Urinary epinephrine and norepinephrine excretions were significantly higher in SHR than in WKY rats and C3 KO SHR. These findings showed that increased C3 induces salt-sensitive hypertension with increases in urinary catecholamine excretion and intrarenal activation of the renin-angiotensin system by the dedifferentiation of mesenchymal tissues in kidney from SHR.

Pathological activation of the renin-angiotensin system and inflammation are associated with hypertension and the development of metabolic syndrome (MetS). The contributions of angiotensin receptor type 1 (AT1) activation, independent of blood pressure, and inflammation to glucose intolerance and renal damage are not well defined. Using a rat model of MetS, we hypothesized that the onset of glucose intolerance is primarily mediated by AT1 activation and inflammation independent of elevated systolic blood pressure (SBP). To address this hypothesis, we measured changes in SBP, adiposity, plasma glucose and triglyceride levels, and glucose tolerance in six groups of rats: 1) lean, strain control Long-Evans Tokushima Otsuka (LETO; n = 5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n = 8), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n = 8), 4) OLETF + tumor necrosis factor-α (TNF-α) inhibitor (ETAN; 1.25 mg etanercept/kg; n = 6), 5) OLETF + TNF-α inhibitor + angiotensin receptor blocker (ETAN+ARB; 1.25 mg etanercept/kg + 10 mg olmesartan/kg; n = 6), and 6) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n = 7). ARB and ETAN+ARB were most effective at decreasing SBP in OLETF, and ETAN did not offer any additional reduction. Glucose tolerance improved in ARB, ETAN, and ETAN+ARB compared with OLETF, whereas CCB had no detectable effect. Furthermore, all treatments reduced adiposity, whereas ETAN alone normalized urinary albumin excretion. These results suggest that AT1 activation and inflammation are primary factors in the development of glucose intolerance in a setting of MetS and that the associated increase in SBP is primarily mediated by AT1 activation.

Hyperphosphatemia accelerates the progression of chronic kidney diseases. In the present study, the effects of ronacaleret, a calcilytic agent, on renal injury were assessed in the following four groups of rats: 5/6-nephrectomized Wistar rats as a control (C group), rats treated with ronacaleret (3 mg·kg−1·day−1; R group), rats treated with calcitriol (30 ng·kg−1·day−1; V group), and rats treated with both ronacaleret and calcitriol (R + V group). Three months later, rats were euthanized under anesthesia, and the remnant kidneys were harvested for analysis. Albuminuria was lower in the R and V groups than in the C group ( P < 0.05). Creatinine clearance was elevated in the R and V groups compared with the C group ( P < 0.05). Serum Ca2+ and renal ANG II were higher in the R + V group than in the C group ( P < 0.05 for each), and serum phosphate was reduced in the R group compared with the C group ( P < 0.05). Fibroblast growth factor-23 was lower in the R group and higher in the V and R + V groups than in the C group. However, parathyroid hormone did not differ significantly among the four groups. Renal klotho expression was elevated in the R and V groups compared with the C group ( P < 0.05). The present data indicate that ronacaleret preserves klotho expression and renal function with reductions in serum phosphate and albuminuria in 5/6-nephrectomized rats. Our findings demonstrate that vitamin D prevents declines in klotho expression and renal function, suppressing albuminuria.

The renal tissue renin-angiotensin system is activated in chronic kidney diseases. We previously demonstrated that intrarenal ANG II is synthesized primarily from liver-derived angiotensinogen filtered through the glomerulus and that podocyte injury increases the passage of angiotensinogen into the tubular lumen and generation of ANG II. In the present study, we tested the effect of cessation of glomerular filtration by ureteral obstruction on renal ANG II generation in kidneys with podocyte injury under two experimental conditions. Ureteral obstruction is known to activate the renin-angiotensin system in nonproteinuric kidneys. Transgenic mice expressing hCD25 in podocyte (NEP25) were injected with 1.25 or 10 ng/g body wt of LMB2, a hCD25-targeted immunotoxin, subjected to unilateral ureteral ligation on the following day, and euthanized 7 and 4 days later, respectively. In both experiments, compared with the kidney in untreated wild-type mice, renal angiotensinogen protein, as assessed by immunostaining and Western blot analysis, was increased in the contralateral unobstructed kidney. However, it was markedly decreased in the obstructed kidney. Whereas intrarenal ANG II content was increased in the contralateral kidney compared with the untreated kidney (248 ± 83 vs. 106 ± 21 and 298 ± 185 vs. 64.8 ± 20 fmol/g kidney, respectively), this increase was suppressed in the obstructed kidney (161 ± 75 and 113 ± 34 fmol/g kidney, respectively), a pattern opposite to what we expected in obstructed kidneys without podocyte injury. Thus, our study indicates that the major source of increased renal ANG II in podocyte injury is filtered angiotensinogen.

Previous studies have reported that high-salt intake paradoxically activates tubuloglomerular feedback (TGF) in type 1 diabetes. Using Zucker lean (ZL) and diabetic fatty (ZDF) rats on normal and high-salt diets, renal hemodynamics and the renin-angiotensin system (RAS) were characterized. On normal salt diet, glomerular filtration rate (GFR) was higher in ZDF than ZL rats. Autoregulation of GFR was less efficient and lithium clearance was lower in ZDF rats than ZL rats. Salt load reduced GFR in ZDF rats with restoration of lithium clearance and partial improvement in autoregulatory index (AI). The administration of 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine-1 receptor antagonist to ZDF rats on a high-salt diet abolished the improvement of AI in GFR. However, this effect was seen by neitherCx40GAP27 norCx37,43GAP27, which inhibits connexin (Cx) 40 or Cx37. Renal ANG II was higher in ZDF than ZL rats on normal salt diet, but the difference was eliminated by a salt load. The present data provide the first demonstration for a salt paradox in type 2 diabetes and implicate that in addition to Cx alterations, an enhanced proximal reabsorption attenuates TGF, underlying glomerular hyperfiltration and RAS activation. These data suggest that a high-salt diet standardizes distal delivery in diabetes, suppressing the RAS, and improving GFR autoregulation and hyperfiltration through adenosine.

Despite suppression of the circulating renin-angiotensin system (RAS), high salt intake (HSI) aggravates kidney injury in chronic kidney disease. To elucidate the effect of HSI on intrarenal RAS, we investigated the levels of intrarenal prorenin, renin, (pro)renin receptor (PRR), receptor-mediated prorenin activation, and ANG II in chronic anti-thymocyte serum (ATS) nephritic rats on HSI. Kidney fibrosis grew more severe in the nephritic rats on HSI than normal salt intake. Despite suppression of plasma renin and ANG II, marked increases in tubular prorenin and renin proteins without concomitant rises in renin mRNA, non-proteolytically activated prorenin, and ANG II were noted in the nephritic rats on HSI. Redistribution of PRR from the cytoplasm to the apical membrane, along with elevated non-proteolytically activated prorenin and ANG II, was observed in the collecting ducts and connecting tubules in the nephritic rats on HSI. Olmesartan decreased cortical prorenin, non-proteolytically activated prorenin and ANG II, and apical membranous PRR in the collecting ducts and connecting tubules, and attenuated the renal lesions. Cell surface trafficking of PRR was enhanced by ANG II and was suppressed by olmesartan in Madin-Darby canine kidney cells. These data suggest the involvement of the ANG II-dependent increase in apical membrane PRR in the augmentation of intrarenal binding of prorenin and renin, followed by nonproteolytic activation of prorenin, enhancement of renin catalytic activity, ANG II generation, and progression of kidney fibrosis in the nephritic rat kidneys on HSI. The origin of the increased tubular prorenin and renin remains to be clarified. Further studies measuring the urinary prorenin and renin are needed.

Recently, a new member of the calcitonin gene-related peptide (CGRP) family, adrenomedullin 2 (AM2) or intermedin (IMD), was identified. AM2/IMD has been shown to have a vasodilator effect in mice and rats and an effect on urine formation in rats. In the present study, we investigated the effects of intravenously infused rat AM2 (rAM2) on blood pressure (BP), heart rate (HR), renal sympathetic nerve activity (RSNA), and renal blood flow (RBF) in conscious unrestrained rats relative to the effects of rat adrenomedullin (rAM) and proadrenomedullin NH2-terminal 20 peptide (rPAMP). Intravenous infusion of rAM2 (5 nmol/kg) significantly decreased BP and increased HR, RSNA, and RBF. These hypotensive and sympathoexcitatory effects diminished after 20 min, and HR returned to control levels 30 min after cessation of the infusion. In contrast, a significant increase in RBF was still evident 60 min after cessation of the peptide infusion. The duration of BP, HR, and RSNA responses was longer with rAM (5 nmol/kg) than with rAM2 infusion, whereas the increases in RBF induced by rAM2 and rAM were similar in their amplitude and duration. Infusion of rPAMP (200 nmol/kg) increased HR and RSNA but had no effect on RBF. Baroreceptor denervation suppressed, but did not diminish, the increases in HR and RSNA to rAM2. These findings indicate that the physiological roles of rAM2 and rAM are similar and that rAM2 also has a long-lasting vasodilator action on the renal vascular bed.

To assess the role of superoxide (O2−) and nitric oxide (NO) interaction in mediating the renal actions of ANG II, we examined the renal responses to intra-arterial infusion of ANG II (0.5 ng·kg−1·min−1) before and during administration of a superoxide dismutase mimetic, tempol (0.5 mg·kg−1·min−1), in the presence or absence of NO synthase inhibitor, nitro-l-arginine (NLA; 50 μg·kg−1·min−1), in anesthetized dogs pretreated with enalaprilat (33 μg·kg−1·min−1). In one group of dogs ( n = 7), ANG II infusion before tempol infusion caused decreases of 24 ± 4% in renal blood flow (RBF), 55 ± 7% in urine flow (V), and 53 ± 8% in urinary sodium excretion (UNaV) with a slight decrease in glomerular filtration rate (GFR; −7.8 ± 3.4%). Tempol infusion alone did not cause significant alterations in RBF, GFR, V, or UNaV; however, ANG II in the presence of tempol caused a smaller degree of decreases in RBF (−12 ± 2%), in V (−16 ± 5%), and in UNaV (−27 ± 10%) with a slight increase in GFR (6.6 ± 2.8%) than the responses observed before tempol. In another group of NLA-treated dogs ( n = 6), tempol infusion also caused significant attenuation in the ANG II-induced responses on RBF (−13 ± 3% vs. −22 ± 7%), GFR (−19 ± 5% vs. −33 ± 3), V (−15 ± 12% vs. −28 ± 4%), and UNaV (−11 ± 14% vs. −32 ± 7%). These data demonstrate that renal responses to ANG II are partly mediated by O2−generation and its interaction with NO. The sodium-retaining effect of ANG II is greatly influenced by O2−generation, particularly in the condition of NO deficiency.

Adenosine vasoconstricts preglomerular arterioles via adenosine A1receptors. Because adenosine also activates adenosine A2receptors, its overall renal vascular actions are complex and not fully understood. The present study was performed to determine the relative contributions of adenosine A1and A2areceptors to the responsiveness of the renal microvasculature to adenosine. Afferent and efferent arteriolar diameters were monitored in vitro using the blood-perfused rat juxtamedullary nephron preparation. Basal afferent and efferent arteriolar diameters averaged 17.1 ± 0.5 ( n = 35) and 17.8 ± 0.5 ( n = 20) μm, respectively. Superfusion with 0.1 and 1 μmol/l adenosine did not significantly alter afferent and efferent arteriolar diameters; however, 10 μmol/l adenosine significantly reduced afferent and efferent arteriolar diameters (−8.2 ± 0.8 and −5.7 ± 0.6%, respectively). The afferent and efferent arteriolar vasoconstrictor responses to adenosine waned at a dose of 100 μmol/l, such that diameters returned to values not significantly different from control within 2 min. During adenosine A1receptor blockade with 8-noradamantan-3-yl-1,3-dipropylxanthine (KW-3902: 10 μmol/l), 10 and 100 μmol/l adenosine significantly increased afferent diameter by, respectively, 8.1 ± 1.2 and 13.7 ± 1.3% ( n = 14) and efferent arteriolar diameter by 6.4 ± 1.3 and 9.3 ± 1.2% ( n = 8). The afferent and efferent arteriolar vasodilatory responses to adenosine in the presence of KW-3902 were significantly attenuated by addition of the adenosine A2areceptor antagonist 1,3-dipropyl-7-methyl-8-(3,4-dimethoxystyryl)xanthine (KF-17837: 15 μmol/l, n = 7 and 6, respectively). The addition of KF-17837 alone significantly enhanced afferent ( n = 15) and efferent ( n = 6) arteriolar vasoconstrictor responses to 1, 10, and 100 μmol/l adenosine. These results indicate the presence of adenosine A1and A2areceptors on afferent and efferent arterioles of juxtamedullary nephrons, such that adenosine A2areceptor-mediated vasodilation partially buffers adenosine-induced vasoconstriction in both pre- and postglomerular segments of the renal microvasculature.

The purpose of the present study was to determine 1) whether different organs undergo similar increase in vascular resistance in Dahl-Iwai salt-sensitive (S) rats, and 2) the effects of chronic oral L-arginine supplementation on the regional hemodynamics in S rats. Male 6-wk-old S rats and salt-resistant (R) rats were maintained on an 8% NaCl chow for 4 wk. One group (S or R rats) was maintained on tap water and the other group (S/Arg or R/Arg rats) received tap water containing L-arginine at a concentration of 1.5%. Organ blood flow and cardiac output were measured with microspheres in the conscious condition. Mean blood pressure in S, S/Arg, R, and R/Arg rats was 159 +/- 5, 138 +/- 3, 111 +/- 4, and 112 +/- 4 mmHg, respectively. Urinary excretion of protein and albumin in S/Arg rats was significantly suppressed compared with S rats. Concerning regional hemodynamics, the flow rate of the kidney was lower in S rats than in R rats, but there were no differences between S and R rats in the flow rates of the brain, heart, lung, liver, spleen, intestine, skeletal muscle, and skin. Thus the renal blood flow was solely reduced in S rats on a high-salt diet. The flow rate of the kidney in S/Arg rats was maintained at a higher level compared with that of S rats. L-Arginine treatment tended to produce a recovery in the urinary excretion of guanosine 3',5'-cyclic monophosphate in S rats, but had no effect in R rats. Thus the supplementation of L-arginine prevented the increase in blood pressure in S rats on a high-salt diet and normalized the abnormality of renal hemodynamics accompanying salt-induced hypertension.

Activation of angiotensin receptor type 1 (AT1) contributes to NADPH oxidase (Nox)-derived oxidative stress during metabolic syndrome. However, the specific role of AT1 in modulating redox signaling, mitochondrial function, and oxidative stress in the heart remains more elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing redox signaling and mitochondrial function in the heart during diet-induced insulin resistance in obese animals, Otsuka Long Evans Tokushima Fatty (OLETF) rats ( n = 8/group) were treated with the AT1 blocker (ARB) olmesartan for 6 wk. Cardiac Nox2 protein expression increased 40% in OLETF compared with age-matched, lean, strain-control Long Evans Tokushima Otsuka (LETO) rats, while mRNA and protein expression of the H2O2-producing Nox4 increased 40–100%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized the increased levels of protein and lipid oxidation (nitrotyrosine, 4-hydroxynonenal) and increased the redox-sensitive transcription factor Nrf2 by 30% and the activity of antioxidant enzymes (SOD, catalase, GPx) by 50–70%. Citrate synthase (CS) and succinate dehydrogenase (SDH) activities decreased 60–70%, whereas cardiac succinate levels decreased 35% in OLETF compared with LETO, suggesting that mitochondrial function in the heart is impaired during obesity-induced insulin resistance. ARB treatment normalized CS and SDH activities, as well as succinate levels, while increasing AMPK and normalizing Akt, suggesting that AT1 activation also impairs cellular metabolism in the diabetic heart. These data suggest that the cardiovascular complications associated with metabolic syndrome may result from AT1 receptor-mediated Nox2 activation leading to impaired redox signaling, mitochondrial activity, and dysregulation of cellular metabolism in the heart.

the macula densa cells comprise the sensing component of the tubuloglomerular feedback (TGF) mechanism and respond to changes in tubular fluid composition by transmitting signals to the afferent arterioles thus regulating the preglomerular vascular resistance and filtered load to the tubules ([14][1

schnermann makes several strong points in his article “Adenosine mediates tubuloglomerular feedback responses” ([19][1]). We completely agree that the data provided by two independent laboratories demonstrating that tubuloglomerular feedback (TGF) responses to increases in distal perfusion rate