Renal Arterioles Research Articles

Renoprotective effects of GLP-1 receptor agonists and SGLT-2 inhibitors-is hemodynamics the key point?

Two novel treatments for diabetic kidney disease have emerged after decades with little progression. Both agents were developed for improved glycemic control in patients with type-2 diabetes. However, large clinical trials showed renoprotective effects beyond their ability to lower plasma glucose levels, body weight, and blood pressure. How this renal protection occurs is unknown. We will discuss their physiological effects, with special focus on the renal effects. We discuss how these drugs affect the function of the diabetic and nondiabetic kidneys to elucidate mechanisms by which the renoprotection could arise. Diabetic kidney disease affects the glomerular capillaries, which are usually protected by the renal autoregulatory mechanisms, the myogenic response, and the tubuloglomerular feedback mechanism. Animal models with reduced renal autoregulatory capacity develop chronic kidney disease. Despite different cellular targets, both drugs are suspected to affect renal hemodynamics through changes in the renal autoregulatory mechanisms. The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert a direct vasodilatory effect on the afferent arteriole (AA) positioned just before the glomerulus. Paradoxically, this effect is expected to increase glomerular capillary pressure, causing glomerular injury. In contrast, the sodium-glucose transporter-2 inhibitors (SGLT2i) are believed to activate the tubuloglomerular feedback mechanism to elicit vasoconstriction of the afferent arteriole. Because of their opposing effects on the renal afferent arterioles, it appears unlikely that their renoprotective effects can be explained by common effects of renal hemodynamics, but both drugs appear to add protection to the kidney beyond what can be obtained with classical treatment targeted at lowering blood glucose levels and blood pressure.

Piezo1 Mediates Vasodilation Induced by Acute Hyperglycemia in Mouse Renal Arteries and Microvessels.

Acute hyperglycemia is a risk factor for developing acute kidney injury and poor renal outcome in critically ill patients, whereby the role of renal vasculature remains unclear. We hypothesize that hyperglycemia-associated hyperosmolarity facilitates vasodilation through Piezo1-mediated eNOS (endothelial NO synthase) activation. Vasoreactivity was analyzed using wire myography in isolated mouse mesenteric arteries and renal interlobar, and using microvascular perfusion in renal afferent arterioles and efferent arterioles, and vasa recta. Immunofluorescence and Western blot were used for molecular analyses of isolated mouse blood vessels and human umbilical vein endothelial cells. Pretreatment with hyperglycemia (44 mmol/L glucose; 4 hours) increased acetylcholine-induced relaxation in interlobar arteries and mesenteric arteries, which was prevented by eNOS inhibition using Nω-nitro-L-arginine methylester hydrochloride. Hyperosmotic mannitol solution had a similar effect. Hyperglycemia induced an immediate, Nω-nitro-L-arginine methylester hydrochloride-inhibitable dilation in afferent arterioles, efferent arterioles, and vasa recta, whereby stronger dilation in afferent arterioles compared to efferent arterioles. Hyperglycemia also increased glomerular filtration rate in mice. In human umbilical vein endothelial cells, hyperglycemia, and the Piezo1 activator Yoda-1 increased levels of Piezo1 protein, p-CaMKII (phosphorylated Ca2+/Calmodulin-dependent protein kinase type II), Akt, and p-eNOS (phosphorylated eNOS). The hyperglycemia effect could be prevented by inhibiting Piezo1 using GsMTx4 (Grammostola spatulata mechanotoxin 4) and CaMKII using KN93. Furthermore, in arteries and microvessels, inhibition of Piezo1 using GsMTx4 prevented the hyperglycemia -effect, while Yoda-1 caused relaxation and dilation, respectively. Results reveal that Piezo1 mediates renal vasodilation induced by hyperosmolarity in acute hyperglycemia. This mechanism may contribute to the pathogenesis of renal damage by acute hyperglycemia.

A novel role for the histone modifier PRDM6 and an opportunity to understand hypertension

Renin-secreting cells are critical for survival. These cells control blood pressure (BP), fluid-electrolyte homeostasis, tissue perfusion, kidney development, and repair of damaged glomeruli 1 Sequeira-Lopez M.L.S. Gomez R.A. Renin cells, the kidney, and hypertension. Circulation Research. 2021; 128: 887-907 Crossref PubMed Scopus (12) Google Scholar . Renin-secreting cells descend from mesodermal-derived precursors that differentiate into the mural cells of the kidney arterial tree 1 Sequeira-Lopez M.L.S. Gomez R.A. Renin cells, the kidney, and hypertension. Circulation Research. 2021; 128: 887-907 Crossref PubMed Scopus (12) Google Scholar . Mature renin-secreting cells are confined to the tips of the renal arterioles near the glomeruli, thus their name juxtaglomerular (JG) cells 1 Sequeira-Lopez M.L.S. Gomez R.A. Renin cells, the kidney, and hypertension. Circulation Research. 2021; 128: 887-907 Crossref PubMed Scopus (12) Google Scholar (Figure 1a). Other renin-lineage cells along the afferent arterioles can re-express renin in response to decreased kidney perfusion or fluid losses, resulting in an increased number of renin-secreting cells to restore homeostasis 1 Sequeira-Lopez M.L.S. Gomez R.A. Renin cells, the kidney, and hypertension. Circulation Research. 2021; 128: 887-907 Crossref PubMed Scopus (12) Google Scholar . Understanding how these cells differentiate and regulate renin expression and release may improve the management of hypertension and cardiovascular and kidney diseases. In a recent article published in the Journal of Clinical Investigation, Gunawardhana and colleagues present a novel approach to study the underlying mechanisms of hypertension and hypothesize a possible role for the vascular smooth muscle cell gene Prdm6 in determining the abundance of renin-secreting cells. 2 Gunawardhana K.L. Hong L. Rugira T. Uebbing S. Kucharczak J. Mehta S. Karunamuni D.R. Cabera-Mendoza B. Gandotra N. Scharfe C. Polimanti R. Noonan J.P. Mani A. A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension. The Journal of Clinical Investigation. 2023; : 133 Google Scholar

An Evolutionarily Conserved Olfactory Receptor Is Required for Sex Differences in Blood Pressure

Olfactory receptor 558 (Olfr558) is expressed in the kidney where its functional role is unknown. Using RNAScope, we find that Olfr558 localizes to vascular smooth muscle, including the renal afferent arteriole. Thus, we measured blood pressure (BP) in Olfr558 wild-type (WT) and knockout (KO) mice. Systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP) were measured in whole-body Olfr558 wild-type (WT) and knockout (KO) via telemetry. It is known that males have a higher BP than premenopausal females in both humans and mice; indeed, we find Olfr558WT males (M) have higher BP than females (F, n=7-9 per group), including MAP (M:101.0±1.6 vs. F:89.0±0.9 mmHg, p<0.0001), SBP (M:113±2 vs. F:102±1mmHg, p=0.0025), and DBP (M: 89±2 vs. F:75±01mmHg, p<0.0001). However, sex differences in BP are entirely absent in Olfr558 KO (MAP M: 96±2 vs. F: 95±1mmHg; SBP M: 110±2 vs. F: 108±2mmHg; DBP M: 81±2 vs. F: 82±2mmHg). Of note, other sex differences (body weight) are intact in KO, and KO males and females are fertile. To characterize this phenotype, renin expression was analyzed by qPCR, plasma renin activity (PRA) was measured by ELISA, and vasoreactivity was examined ex vivo by wire myography (responses to potassium chloride (KCl), phenylephrine (PE), acetylcholine (Ach), and sodium nitroprusside (SNP) in aortic and mesenteric rings). In male KOs (n=10-12), there was a decrease in kidney renin mRNA (0.4±0.1 vs WT: 1±0.1 p=0.001) and PRA (201±21 vs WT: 402±15, p=0.001); these parameters were unchanged in female KOs. Male KO aortic rings exhibit less constriction to PE, male KO mesenterics exhibit more relaxation to SNP, and female KO aortic rings exhibit more constriction to KCl. In females, pulse wave velocity (PWV) and tensile testing revealed that KO females have increased PWV (KO: 4.6±0.4 vs WT: 3.2±0.2 m/s, p=0.0069, n=8-11), but no changes in tensile testing. The human ortholog of Olfr558, OR51E1, was previously identified as a locus associated with DBP. Using UK Biobank data (N~450k), we find that a rare OR51E1 missense variant has a statistically significant sex interaction effect with DBP ( p=0.015), increasing DBP (+6.28mmHg) in women but decreasing it (-4.77mmHg) in men (similar to the phenotype in M and F Olfr558 KO mice). Finally, we express OR51E1 variants in HEK 293T cells and characterize how two different clinically relevant OR51E1 variants influence OR51E1 signaling. In sum, our findings demonstrate that an evolutionarily conserved olfactory receptor is required for sex differences in BP. Olfr558 regulates BP in males via renin and vascular reactivity, but via arterial stiffness in females. Funding: R56DK107726 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.

A Cross-Sectional Study of p66Shc Gene Expression in Liquid Biopsy of Diabetic Patients. Is it Possible to Predict the Onset of Renal Disease?

Background: Diabetic nephropathy (DN) is a disorder affecting glomerular function that, histologically, is due to the presence of glomerulosclerosis accompanied with endothelial dysfunction of the afferent and efferent renal arterioles. Insulin resistance in diabetic patients is known to be one of the causes of endothelial dysfunction because it increases oxidative stress, and one of the main genes regulating the production pathways of reactive oxygen species is p66Shc. The aim of this study was to evaluate the p66Shc gene expression as a precocious biomarker of renal dysfunction in diabetic patients, using liquids samples of urine sediment and peripheral blood. Methods: 29 diabetic patients and 37 healthy donors were recruited from the Centro Universitário FMABC outpatient clinic. The RT-gPCR technique was applied to evaluate p66Shc gene expression in urine and peripheral blood samples from diabetic patients, which were compared with healthy donors. Results: There was no significant expression of p66Shc gene in samples from diabetic patients compared with healthy donors. However, p66Shc expression in the blood samples of diabetics (0.02417±0.078652-ΔCT, n=29) was 3.6 times higher than in healthy participants (0.00689±0.01758, n=37) while in the urine samples, it was 1.48 times higher in diabetics group (0.02761±0.05412-ΔCT) than in CTL group (0.0186±0.02199). Conclusion: There was no significant p66Shc gene expression in peripheral blood and urine samples of diabetic patients without kidney injury compared with healthy donors, although there is a tendency for this gene to participate in the oxidative imbalance present in diabetes.

Reactivity of renal and mesenteric resistance vessels to angiotensin II is mediated by NOXA1/NOX1 and superoxide signaling.

Activation of NADPH oxidase (NOX) enzymes and the generation of reactive oxygen species and oxidative stress regulate vascular and renal function and contribute to the pathogenesis of hypertension. The present study examined the role of NOXA1/NOX1 function in vascular reactivity of renal and mesenteric resistance arteries/arterioles of wild-type and Noxa1-/- mice. A major finding was that renal blood flow is less sensitive to acute stimulation by angiotensin II (ANG II) in Noxa1-/- mice compared with wild-type mice, with a direct action on resistance arterioles independent of nitric oxide (NO) bioavailability. These functional results were reinforced by immunofluorescence evidence of NOXA1/NOX1 protein presence in renal arteries, afferent arterioles, and glomeruli as well as their upregulation by ANG II. In contrast, the renal vascular response to the thromboxane mimetic U46619 was effectively blunted by NO and was similar in both mouse genotypes and thus independent of NOXA1/NOX1 signaling. However, phenylephrine- and ANG II-induced contraction of isolated mesenteric arteries was less pronounced and buffering of vasoconstriction after acetylcholine and nitroprusside stimulation was reduced in Noxa1-/- mice, suggesting endothelial NO-dependent mechanisms. An involvement of NOXA1/NOX1/O2•- signaling in response to ANG II was demonstrated with the specific NOXA1/NOX1 assembly inhibitor C25 and the nonspecific NOX inhibitor diphenyleneiodonium chloride in cultured vascular smooth muscle cells and isolated mesenteric resistance arteries. Collectively, our data indicate that the NOX1/NOXA1/O2•- pathway contributes to acute vasoconstriction induced by ANG II in renal and mesenteric vascular beds and may contribute to ANG II-induced hypertension.NEW & NOTEWORTHY Renal reactivity to angiotensin II (ANG II) is mediated by superoxide signaling produced by NADPH oxidase (NOX)A1/NOX1. Acute vasoconstriction of renal arteries by ANG was blunted in Noxa1-/- compared with wild-type mice. NOXA1/NOX1/O2•- signaling was also observed in ANG II stimulation of vascular smooth muscle cells and isolated mesenteric resistance arteries, indicating that it contributes to ANG II-induced hypertension. A NOXA1/NOX1 assembly inhibitor (C25) has been characterized that inhibits superoxide production and ameliorates the effects of ANG II.

PS-R05-3: SEVERE GLOMERULAR MICROANGIOPATHY IN A PATIENT WITH NEPHROTIC SYNDROME FOLLOWING TAKAYASU ARTERITIS

Introduction: Takayasu arteritis (TA) is a large vessel inflammation that predominantly involves aorta and its main arteries. TA-caused kidney injury is known to be mainly due to renal artery stenosis. However, glomerulonephritis including membranous proliferative glomerulonephritis, focal segmental sclerosis, or crescentic nephritis has been histologically identified in some TA cases. Case description: A 69-year-old female presented with leg edema and refractory hypertension with nephrotic range proteinuria (17.0 g/gCr). She exhibited > 10 mmHg blood pressure discrepancy between left and right upper limbs and severe aortic regurgitation. Lab test showed high level of C-reactive protein and high erythrocyte sedimentation rate. Contrast-enhanced computed tomography identified wall thickening of the left subclavian artery, which led to the diagnosis of TA. Renal biopsy demonstrated that double basement membrane, enlarged subendothelial space, and mesangiolysis with no immunoglobulin deposition. Although azilsartan 40 mg QD and nifedipine 30 mg BID had been prescribed, systolic blood pressure (sBP) was still > 160 mmHg. Thus, while oral prednisolone was started to suppress TA-induced inflammation, azilsartan was replaced with sacubitril valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), for treating refractory hypertension. After a few weeks, sBP was decreased to 130 mmHg with sacubitril valsartan 200 mg QD and proteinuria was dramatically improved to 0.5 g/gCr. Discussion: TA commonly involves the renal artery, leading to stenosis and subsequent ischemic nephropathy. However, no stenosis and occlusion were observed in renal artery of this case. In addition, small vessel inflammation in the kidney such as vessel wall necrosis and immune cells infiltration around arterioles was not found. Serum levels of pro-inflammatory cytokines including vascular endothelial growth factor and interleukin-6, a well-known contributors for progression of TA-related inflammation, were within the normal range. The results indicate that TA-caused hypertension, but not vessel inflammation induced by TA, seems to play a pathological role for development of glomerular microangiopathy in this case. A previous study showed that 70% of TA patients presenting with glomerular lesion has severe hypertension and intimal thickening in renal arterioles was observed more frequently in TA patients presenting with glomerular lesion when compared to those without glomerulonephritis, which supports our hypothesis. In the present case, ARNI significantly reduced sBP which might directly contribute to the improvement of proteinuria. ARNI can be potent to control hypertension more effectively than conventional hypertensive agents in TA patients.

Localization of natriuretic peptide receptors A, B, and C in healthy and diseased mouse kidneys

The natriuretic peptides (NPs) ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) mediate their widespread effects by activating the natriuretic peptide receptor-A (NPR-A), while C-type natriuretic peptide (CNP) acts via natriuretic peptide receptor-B (NPR-B). NPs are removed from the circulation by internalization via the natriuretic peptide clearance receptor natriuretic peptide receptor-C (NPR-C). In addition to their well-known functions, for instance on blood pressure, all three NPs confer significant cardioprotection and renoprotection. Since neither the NP-mediated renal functions nor the renal target cells of renoprotection are completely understood, we performed systematic localization studies of NP receptors using in situ hybridization (RNAscope) in mouse kidneys. NPR-A mRNA is highly expressed in glomeruli (mainly podocytes), renal arterioles, endothelial cells of peritubular capillaries, and PDGFR-receptor β positive (PDGFR-β) interstitial cells. No NPR-A mRNA was detected by RNAscope in the tubular system. In contrast, NPR-B expression is highest in proximal tubules. NPR-C is located in glomeruli (mainly podocytes), in endothelial cells and PDGFR-β positive cells. To test for a possible regulation of NPRs in kidney diseases, their distribution was studied in adenine nephropathy. Signal intensity of NPR-A and NPR-B mRNA was reduced while their spatial distribution was unaltered compared with healthy kidneys. In contrast, NPR-C mRNA signal was markedly enhanced in cell clusters of myofibroblasts in fibrotic areas of adenine kidneys. In conclusion, the primary renal targets of ANP and BNP are glomerular, vascular, and interstitial cells but not the tubular compartment, while the CNP receptor NPR-B is highly expressed in proximal tubules. Further studies are needed to clarify the function and interplay of this specific receptor expression pattern.

Acute Calcineurin Inhibitor Nephrotoxicity Diagnosed Using Kidney Doppler Ultrasonography After Heart Transplant: A Case Report

Acute calcineurin inhibitor (CNI) nephrotoxicity is a common complication associated with CNI exposure. However, it can be difficult to diagnose. Herein, we report a case of acute CNI nephrotoxicity after heart transplant that was visualized using kidney Doppler ultrasonography. A 38-year-old female patient underwent heart transplant 5 years after the use of left ventricular assist device support because of advanced heart failure due to ischemic cardiomyopathy. Corticosteroids, tacrolimus, and mycophenolate mofetil were administered as immunosuppressive regimens postoperatively. The patient gradually developed kidney dysfunction despite a favorable perioperative clinical course and hemodynamics. Serum creatinine increased to 1.89 mg/dL on postoperative day (POD) 9, and the kidney Doppler ultrasonography examination showed severely reduced blood flow in the renal and renal segmental arteries, indicating acute CNI nephrotoxicity due to vasoconstriction of the renal arterioles. After the cessation of tacrolimus, kidney function returned to baseline levels within 2 days, and the kidney Doppler ultrasonography examination on POD 19 revealed a significant increase in blood flow in the renal and renal segmental arteries. Basiliximab followed by everolimus were administered as alternative immunosuppressants. No organic stenosis of the renal artery was detected on the kidney magnetic resonance angiography, and the patient was discharged on POD 51, without any other adverse events, including rejection. Although CNIs are widely used after heart transplant, acute nephrotoxicity should always be considered. After heart transplant, a kidney Doppler ultrasonography should be performed routinely and promptly if there are any clinical manifestations related to kidney function.

Tacrolimus Causes Hypertension by Increasing Vascular Contractility via RhoA (Ras Homolog Family Member A)/ROCK (Rho-Associated Protein Kinase) Pathway in Mice.

To provide tacrolimus is first-line treatment after liver and kidney transplantation. However, hypertension and nephrotoxicity are common tacrolimus side effects that limit its use. Although tacrolimus-related hypertension is well known, the underlying mechanisms are not. Here, we test whether tacrolimus-induced hypertension involves the RhoA (Ras homolog family member A)/ROCK (Rho-associated protein kinase) pathway in male C57Bl/6 mice. Intra-arterial blood pressure was measured under anesthesia. The reactivity of renal afferent arterioles and mesenteric arteries were assessed in vitro using microperfusion and wire myography, respectively. Tacrolimus induced a transient rise in systolic arterial pressure that was blocked by the RhoA/ROCK inhibitor Fasudil (12.0±0.9 versus 3.2±0.7; P<0.001). Moreover, tacrolimus reduced the glomerular filtration rate, which was also prevented by Fasudil (187±20 versus 281±8.5; P<0.001). Interestingly, tacrolimus enhanced the sensitivity of afferent arterioles and mesenteric arteries to Ang II (angiotensin II), likely due to increased intracellular Ca2+ mobilization and sensitization. Fasudil prevented increased Ang II-sensitivity and blocked Ca2+ mobilization and sensitization. Preincubation of mouse aortic vascular smooth muscle cells with tacrolimus activated the RhoA/ROCK/MYPT-1 (myosin phosphatase targeting subunit 1) pathway. Further, tacrolimus increased cytoplasmic reactive oxygen species generation in afferent arterioles (107±5.9 versus 163±6.4; P<0.001) and in cultured mouse aortic vascular smooth muscle cells (100±7.5 versus 160±23.2; P<0.01). Finally, the reactive oxygen species scavenger Tempol inhibited tacrolimus-induced Ang II hypersensitivity in afferent arterioles and mesenteric arteries. The RhoA/ROCK pathway may play an important role in tacrolimus-induced hypertension by enhancing Ang II-specific vasoconstriction, and reactive oxygen species may participate in this process by activating the RhoA/ROCK pathway.

The Relationship Between Klotho and SIRT1 Expression in Renal Aging Related Disease.

BackgroundThis study focused on renal arteriosclerosis and aimed to explore the relationship between Klotho and SIRT1 by morphological staining, which will help to provide new ideas for the treatment of renal-aging-related diseases and a theoretical basis for the development of new drugs.MethodsKidney tissue samples were collected from patients who underwent nephrectomy. HK-2 cells were cultured. The Hematoxylin-eosin (HE) staining, Periodic Acid-Schiff (PAS) staining, Masson’s Trichrome staining, Immunohistochemistry (IHC) staining, Immunofluorescence (ICC) and bioinformatics means were used for this study.ResultsHE staining showed that glomerulosclerosis was atrophic and cast was significantly increased luminal narrowing of renal arterioles in aging group. PAS staining showed that the number of podocytes was reduced, the mesangial matrix expansion and the intimal fibrosis of renal arterioles. Masson’s trichrome staining showed that there was massive collagen proliferation in the tubulointerstitial in aging group, as well as intimal thickening and fibrin deposition in the tubular walls of arterioles. IHC staining showed that the expression of Klotho and SIRT1 protein was downregulated in aging group and the trend of the two was positively correlated (P < 0.01). Klotho and SIRT1 co-localized in HK-2 cells and kidney tissue. The GEPIA database analysis showed a significant positive correlation between Klotho and SIRT1 in multiple human tissues and tumors.ConclusionGlomerulosclerosis in aging group is accompanied by low expression of Klotho and SIRT1 in renal tissue, and Klotho is positively correlated with SIRT1. Klotho-SIRT1 pathway may be involved in the occurrence and development of renal-aging-related diseases.

Abstract 011: Epigenetic Determinants Of Renin Cell Identity

Renin secreting cells are restricted in adult mammals within the walls of renal arterioles near the entrance to the glomeruli and are therefore known as juxtaglomerular (JG) cells. These JG cells are critical for survival through the maintenance of homeostasis via the release of the peptide hormone renin in response to changes in blood pressure. By performing independently paired scATAC-seq and scRNA-seq during mouse kidney development, we sought to identify epigenetic markers of renin cell identity. While we lack spatial information, we identified putative JG cells through the identification of cells enriched in canonical markers (Ren1 and Akr1b7) of JG cell identity using both expression and accessibility derived measures of gene activity. We constructed a pseudotime trajectory of cells that lead to the mature JG population and performed pairwise comparisons of cell populations to identify the genomic regions and transcription factors (TFs) contributing to JG cell identity. As JG cells form along this trajectory, significantly different (Log2FC&gt;0.5 and FDR&lt;0.1) regions of accessible chromatin define the JG cell population. Within these open regions, the MEF2 family of TF motifs are significantly enriched (log10Padj &gt; 20). We further identify a specific region of accessible chromatin (chr1:133345385-133345885) unique to the initial population of JG cells located within a Ren1 super enhancer previously identified by our group. This region is co-accessible with several regions of open chromatin within the greater Ren1 gene region (correlation &gt; 0.75) where we identify putative binding sites for Mef2b, 2c, and 2d at these co-accessible regions. As the mature renin-expressing cells further differentiate into terminally differentiated cell populations including pericytes and mesangial cells, we continue to see significant enrichment of the MEF2 TF family within the JG cell population compared to downstream populations (log10Padj &gt; 646.6891). Overall, we have presented the first investigation and finding using single-cell -omics of the JG cell population and uncover the importance of the MEF2 family of TFs as significant drivers of JG cell formation and identity.

Age-related Changes in Renal Arterio-Arteriolosclerosis in Kidney Disease: Renal Biopsy-based Study

Age-related Changes in Renal Arterio-Arteriolosclerosis in Kidney Disease: Renal Biopsy-based Study

THE IMPORTANCE OF EARLY DIAGNOSIS OF MALIGNANT HYPERTENSION - CASE REPORT

Malignant hypertension is a syndrome consisting of severe arterial hypertension, retinopathy with papilledema (with or without renal failure) and fibrinoid necrosis of renal arterioles, which may present a rapidly progressive and fatal clinical course. In this pathology may occur vascular lesions that consist mainly of myointimal proliferation and arteriolar fibrinoid necrosis, which can develop acutely and compromise the light from the small blood vessels. The prognosis of malignant hypertension is almost always fatal if it is not recognized or not adequately treated, with a mortality rate of about 80% in 2 years, mainly as a result of progression into heart failure syndrome and end-stage renal failure syndrome

Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease.

In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an abnormally elevated glomerular filtration rate. Glomerular hyperfiltration is an independent risk factor for accelerated deterioration of renal function and progression of nephropathy, which is associated with a high risk for metabolic and cardiovascular disease. It is imperative to understand hyperfiltration and identify potential treatments to delay DKD progress. This paper summarizes the current mechanisms of hyperfiltration in early DKD. We pay close attention to the effect of glucose reabsorption mediated by sodium–glucose cotransporters and renal growth on hyperfiltration in DKD patients, as well as the mechanisms of nitric oxide and adenosine actions on renal afferent arterioles via tubuloglomerular feedback. Furthermore, we also focus on the contribution of the atrial natriuretic peptide, cyclooxygenase, renin–angiotensin–aldosterone system, and endothelin on hyperfiltration. Proposing potential treatments based on these mechanisms may offer new therapeutic opportunities to reduce the renal burden in this population.

The Role of Complement in Microangiopathic Lesions of IgA Nephropathy

IntroductionArteriolar microangiopathic (MA) lesions are independent risk factors for IgA nephropathy (IgAN) patient prognosis, and the underlying mechanism remains to be elucidated. The complement plays an important role in IgAN and thrombotic microangiopathy; however, its role in MA lesions in IgAN remains unclear.MethodsImmunohistochemistry was performed to detect arteriolar complement deposition. Enzyme-linked immunosorbent assay (ELISA) and whole-exome sequencing were performed to explore possible mechanism.ResultsIn this study, we found that patients with IgAN with MA lesions have more complement deposition, especially C4d, on renal arterioles than those in patients with arteriolosclerosis (AS) and patients with no vascular lesions (100% vs. 53% vs. 14%, P < 0.05). Furthermore, our large prospective cohort demonstrated that patients with IgAN with MA lesions had higher levels of Gd-IgA1 (median: 326.98 U/ml, interquartile range 303.46–370.5 vs. 319.22, 292.01–347.3 vs. 321.95, 291.68–350.68, P = 0.014) and C3a (122.57 ± 42.07 vs. 93.79 ± 29.49 vs. 93.51 ± 45.87 ng/ml, P = 0.01) than those in patients with AS and those with no vascular lesions. However, serum IgA1 and C3 levels were not significantly different. Finally, through whole-exome sequencing, we found that nearly half of the patients with MA lesions had rare genetic variations in complement-related genes.ConclusionOur results indicate that the complement is involved in the development of MA lesions in IgAN, which might be associated with the circulating complex containing Gd-IgA1.

βENaC and ASIC2 associate in VSMCs to mediate pressure-induced constriction in the renal afferent arteriole.

In independent studies, our laboratory has shown the importance of the degenerin proteins β-epithelial Na+ channel (βENaC) and acid-sensing ion channel 2 (ASIC2) in pressure-induced constriction (PIC) in renal interlobar arteries. Most, but not all, of the PIC response is abolished in mice lacking normal levels of βENaC or in ASIC2-null mice, indicating that the functions of βENaC and ASIC2 cannot fully compensate for the loss of the other. Degenerin proteins are known to associate and form heteromeric channels in expression systems, but whether they interact biochemically and functionally in vascular smooth muscle cells is unknown. We hypothesized that βENaC and ASIC2 interact to mediate PIC responses in renal vessels. To address this possibility, we 1) used biochemical approaches to show that βENaC associates into high-molecular-weight complexes and immunoprecipitants with ASIC2 in vascular smooth muscle cells and then 2) examined PIC in renal afferent arterioles in mice lacking normal levels of βENaC (βENaCm/m) or/and ASIC2 (ASIC2-/-) using the isolated afferent arteriole-attached glomerulus preparation. We found that the sensitivity of the PIC response (slope of the relationship between intraluminal pressure and percent myogenic tone) decreased to 26%, 27%, and -8% of wild-type controls in ASIC2-/-, βENaCm/m, and ASIC2-/-/βENaCm/m groups, respectively, suggesting that the PIC response was totally abolished in mice deficient in both ASIC2 and βENaC. Surprisingly, we found that resting internal diameters were 20-30% lower (60 mmHg, Ca2+ free) in ASIC2-/-/βENaCm/m (11.3 ± 0.5 µm) mice compared with control (14.4 ± 0.6 µm, P = 0.0007, independent two-tailed t test) or singly modified (15.7 ± 1.0 to 16.3 ± 1.1 µm) mice, suggesting compensatory vasoconstriction or remodeling. We then examined mean arterial blood pressure (MAP) using radiotelemetry and glomerular injury using histological examination of renal sections. We found that 24-h MAP was mildly elevated (+8 mmHg) in ASIC2-/-/βENaCm/m mice versus wild-type controls and the glomerular injury score was modestly increased by 38%. These findings demonstrate that myogenic constriction in afferent arterioles is dependent on normal expression of βENaC and ASIC2 and that mice lacking normal levels of ASIC2 and βENaC have mild renal injury and increased MAP.NEW & NOTEWORTHY Transmission of systemic blood pressure to delicate renal microvessels is a primary determinant of vascular injury in chronic kidney disease progression to end-stage renal disease. Here, we identified two degenerin family members, with an evolutionary link to mechanosensing, that interact biochemically and functionally to regulate systemic blood pressure and renal injury. Thus, degenerin proteins may serve as a target for the development of therapies to prevent or delay renal disease progression.

Biopsy-proven kidney involvement in hypocomplementemic urticarial vasculitis

BackgroundHypocomplementemic urticarial vasculitis (HUV) is a rare systemic vasculitis. We aimed to describe the kidney involvement of HUV in a multicenter national cohort with an extended follow-up.MethodsAll patients with HUV (international Schwartz criteria) with a biopsy-proven kidney involvement, identified through a survey of the French Vasculitis Study Group (FVSG), were included. A systematic literature review on kidney involvement of HUV was performed.ResultsTwelve patients were included, among whom 8 had positive anti-C1q antibodies. All presented with proteinuria, from mild to nephrotic, and 8 displayed acute kidney injury (AKI), requiring temporary haemodialysis in 2. Kidney biopsy showed membrano-proliferative glomerulonephritis (MPGN) in 8 patients, pauci-immune crescentic GN or necrotizing vasculitis in 3 patients (with a mild to severe interstitial inflammation), and an isolated interstitial nephritis in 1 patient. C1q deposits were observed in the glomeruli (n = 6), tubules (n = 4) or renal arterioles (n = 3) of 8 patients. All patients received corticosteroids, and 9 were also treated with immunosuppressants or apheresis. After a mean follow-up of 8.9 years, 6 patients had a preserved renal function, but 2 patients had developed stage 3–4 chronic kidney disease (CKD) and 4 patients had reached end-stage kidney disease (ESKD), among whom 1 had received a kidney transplant.ConclusionRenal involvement of HUV can be responsible for severe AKI, CKD and ESRD. It is not always associated with circulating anti-C1q antibodies. Kidney biopsy shows mostly MPGN or crescentic GN, with frequent C1q deposits in the glomeruli, tubules or arterioles.

Neopioidni analgetici u terapiji bola kritično obolelih pacijenata - prijatelji, neprijatelji ili dobri saradnici?

Patients in intensive care units (ICUs) experience pain, which they describe as a significant cause of stress during treatment. It can progress to chronic pain and significantly affect the quality of life. Opioids have long been the backbone of ICU pain therapy. The consequences of their long-term use are known today, such as prolonged ICU stay and mechanical ventilation, resulting in increased treatment costs. Additionally, abstinence syndrome is a consequence of abrupt opioid withdrawal. Also, there is a risk of tolerance and hyperalgesia after prolonged opioid use. Globally, opioid dependence after hospital opioid treatment is alarming, although there is still a lack of data on its incidence after ICU. Multimodal analgesia enables comfort to the patient, opioid-sparing, and avoidance of side effects of non-opioid analgesics. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a broad group of drugs recommended with paracetamol to treat mild to moderate acute postoperative pain. Although often prescribed by intensivists, their use in treating painful conditions in ICU is controversial due to the possible consequences on the organs of critically ill patients. Due to the inhibition of cyclooxygenases, NSAIDs indirectly cause vasoconstriction of the renal arteries and arterioles, leading to kidney damage. NSAIDs inhibit platelet aggregation and may predispose to bleeding. Analgesia of a critically ill patient is a important part of their treatment, however it can be challenging in certain patients. Numerous combinations of pharmacological and non-pharmacological approaches can be adapted to the patient's current characteristics.

Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans.

Inhibitors of the renin-angiotensin system (RAS) are widely used to treat hypertension. Using mice harboring fluorescent cell lineage tracers, single-cell RNA-Seq, and long-term inhibition of RAS in both mice and humans, we found that deletion of renin or inhibition of the RAS leads to concentric thickening of the intrarenal arteries and arterioles. This severe disease was caused by the multiclonal expansion and transformation of renin cells from a classical endocrine phenotype to a matrix-secretory phenotype: the cells surrounded the vessel walls and induced the accumulation of adjacent smooth muscle cells and extracellular matrix, resulting in blood flow obstruction, focal ischemia, and fibrosis. Ablation of the renin cells via conditional deletion of β1 integrin prevented arteriolar hypertrophy, indicating that renin cells are responsible for vascular disease. Given these findings, prospective morphological studies in humans are necessary to determine the extent of renal vascular damage caused by the widespread use of inhibitors of the RAS.