Search

Background: Renal artery stenosis (RAS) can lead to hypertension and renal failure. Nevertheless, its treatment by percutaneous transluminal renal angioplasty (PTRA) remains controversial. It is unknown, whether patients with global kidney ischemia (GKI), that means patients with bilateral RAS or RAS with a single functioning kidney, may benefit from PTRA or not. Methods: We retrospectively analyzed 93 patients with RAS (25 bilateral or single functioning kidney) undergoing PTRA. Patients had refractory hypertension (≥3 medications). Blood pressure, antihypertensive drugs and serum-creatinine were compared pre-/post-intervention and at 1 year’s follow-up. Results: At 1 year after PTRA of patients with GKI, systolic and diastolic blood pressure were significantly reduced compared to patients with unilateral PTRA (systolic: −19.1 ± 10.5 [bilateral] vs. −11.4 ± 12.1 mmHg [unilateral], P

Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic blood pressure reductions. Clinical trial data available thus far have been obtained primarily in patients with resistant hypertension, defined as standardized systolic clinic blood pressure ≥ 160 mm Hg (or ≥ 150 mm Hg in patients with type 2 diabetes) despite appropriate pharmacologic treatment with at least 3 antihypertensive drugs, including a diuretic agent. Accordingly, these criteria and blood pressure thresholds should be borne in mind when selecting patients for renal nerve ablation. Secondary forms of hypertension and pseudoresistance, such as nonadherence to medication, intolerance of medication, and white coat hypertension, should have been ruled out, and 24-h ambulatory blood pressure monitoring is mandatory in this context. Because there are theoretical concerns with regard to renal safety, selected patients should have preserved renal function, with an estimated glomerular filtration rate ≥ 45 ml/min/1.73 m(2). Optimal periprocedural management of volume status and medication regimens at specialized and experienced centers equipped with adequate infrastructure to cope with potential procedural complications will minimize potential patient risks. Long-term safety and efficacy data are limited to 3 years of follow-up in small patient cohorts, so efforts to monitor treated patients are crucial to define the long-term performance of the procedure. Although renal nerve ablation could have beneficial effects in other conditions characterized by elevated renal sympathetic nerve activity, its potential use for such indications should currently be limited to formal research studies of its safety and efficacy.

Nephrin, the key molecule of the glomerular slit diaphragm, is expressed on the surface of podocytes and is critical in preventing albuminuria. In diabetes, hyperglycemia leads to the loss of surface expression of nephrin and causes albuminuria. Here, we report a mechanism that can explain this phenomenon: hyperglycemia directly enhances the rate of nephrin endocytosis via regulation of the β-arrestin2-nephrin interaction by PKCα. We identified PKCα and protein interacting with c kinase-1 (PICK1) as nephrin-binding proteins. Hyperglycemia induced up-regulation of PKCα and led to the formation of a complex of nephrin, PKCα, PICK1, and β-arrestin2 in vitro and in vivo. Binding of β-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by PKCα. Further, cellular knockdown of PKCα and/or PICK1 attenuated the nephrin-β-arrestin2 interaction and abrogated the amplifying effect of high blood glucose on nephrin endocytosis. In C57BL/6 mice, hyperglycemia over 24 h caused a significant increase in urinary albumin excretion, supporting the concept of the rapid impact of hyperglycemia on glomerular permselectivity. In summary, we have provided a molecular model of hyperglycemia-induced nephrin endocytosis and subsequent proteinuria and highlighted PKCα and PICK1 as promising therapeutic targets for diabetic nephropathy.

Glomerular expression of the ATP-sensitive P2X7 receptor in diabetic and hypertensive rat models.BackgroundThe molecular identification and characterization of the adenosine triphosphate (ATP)-sensitive family of P2 receptors is comparatively new. There are two main subgroups, each with several subtypes and widespread tissue distribution, including the kidney. A unique member of the P2X subgroup of P2 receptors is the ATP-gated ion channel P2X7, which on activation can cause cell blebbing, cytokine release, and cell death by necrosis or apoptosis. We report expression of this receptor in normal rat kidney and in two chronic models of glomerular injury: streptozotocin-induced (STZ) diabetes and ren-2 transgenic (TGR) hypertension.MethodsAt different time points in these models, we used a polyclonal antibody to the P2X7 receptor and immunohistochemistry to determine its expression and distribution. We also used Western blotting and real-time polymerase chain reaction (PCR) to detect changes in P2X7 receptor protein and mRNA expression, respectively.ResultsWe found only low-level glomerular immuno-staining for the P2X7 receptor in normal rat kidney, but intense P2X7 receptor immunostaining of glomeruli in kidneys from diabetic animals at 6 and 9 weeks, and in hypertensive animals at 12 weeks. In diabetic animals, real-time PCR demonstrated a ∼tenfold increase in glomerular P2X7 receptor mRNA relative to control, and Western blotting confirmed an increase in protein. Immunohistochemistry and immunoelectron microscopy showed staining of glomerular podocytes, which was both intracellular and at the plasma membrane.ConclusionWe conclude that the P2X7 receptor is not expressed appreciably under normal conditions, but that following glomerular injury it is significantly up-regulated, mainly in podocytes, though also in endothelial and mesangial cells, of animals with STZ-induced diabetes mellitus or TGR hypertension. Although the exact function and regulation of this receptor remain unclear, its association with inflammatory cytokine release and cell death suggests that increased expression might be involved in the pathogenesis of glomerular cell injury or repair.

ATP release in human kidney cortex and its mitogenic effects in visceral glomerular epithelial cells Background In chronic renal failure the sympathetic nervous system is activated. Sympathetic cotransmitters released within the kidney may contribute to the progression of renal disease through receptor-mediated proliferative mechanisms. Methods In human renal cortex electrical stimulation induced adenosine 5′-triphosphate (ATP; luciferin-luciferase-assay) and norepinephrine (HPLC) release was measured. ATP release also was induced by α 1 - and α 2 -adrenergic agonists. [ 3 H]-thymidine uptake was tested in human visceral glomerular epithelial cells (vGEC) and mitogen-activated protein kinase (MAPK 42/44 ) activation in vGEC and kidney cortex. The involved P2-receptors were characterized pharmacologically and by RT-PCR. Results Sympathetic nerve stimulation and α-adrenergic agonists induced release of ATP from human kidney cortex. Seventy-five percent of the ATP released originated from non-neuronal sources, mainly through activation of α 2 -adrenergic receptors. ATP (1 to 100 μmol/L) and related nucleotides (1 to 100 μmol/L) increased [ 3 H]-thymidine uptake. The adenine nucleotides ATP, ATPγS, ADP and ADPβS were about equally potent. UTP, UDP and α,β-methylene ATP had no effect. ATP, ADPβS but not α,β-methylene ATP activated MAPK 42/44 . ATP induced MAPK 42/44 activation, and [ 3 H]-thymidine uptake was abolished in the presence of the MAPK inhibitor PD 98059 (100 μmol/L). mRNA for P2X 4,5,6,7 and P2Y 1,2,4,6,11 were detected in human vGEC by RT-PCR. Conclusions In human renal cortex, adrenergic stimulation releases ATP from neuronal and non-neuronal sources. ATP has mitogenic effects in vGEC and therefore the potential to contribute to progression in chronic renal disease. The pattern of purinoceptor agonist effects on DNA synthesis together with the mRNA expression suggests a major contribution of a P2Y1-like receptor.

In July, 2011, a 58-year-old man with type II diabetes and hypertension resistant to treatment was referred to our hospital for renal denervation. He had had hypertension for 30 years and his antihypertensive medication dose had been increased over several years. In 2001, he had a minor stroke, and in 2009, a carotid artery stent was implanted. On examination, his blood pressure was 170/90 mm Hg despite treatment with seven antihypertensive drugs (appendix). Resistant hypertension was confi rmed by 24 h ambulatory blood pressure measurement. He also had sleep apnoea which was treated with continuous positive airway pressure therapy. Aldosteronism, phaeochromocytoma, and renal artery stenosis were ruled out. Renal resistive indices (RI) on both sides were similar. Normal renal function with microalbuminuria was present. Magnetic resonance angiography (appendix) done before renal denervation showed early ramifi cation but no relevant stenosis on either side. In August, 2011, six ablations were applied on the left side (three in each branch) and six on the right side, including two at proximal superior positions 4 mm and 9 mm distal to the ostium (fi gure). Ablations were applied in a spiral pattern at a minimum distance of 5 mm. Renal artery alterations were not visible im mediately after denervation. Duplex sonography the next day did not show any abnormalities. 3 months later his blood pressure had decreased to 140/70 mm Hg. A routine follow-up duplex sonography showed turbulences and increased renal blood fl ow velocity on the right side. At this time no diff erences in RI were detectable, excluding