Hyperglycemia-induced Renal P2X7 Receptor Activation Enhances Diabetes-related Injury

Diabetes is a leading cause of renal disease. Glomerular mesangial expansion and fibrosis are hallmarks of diabetic nephropathy and this is thought to be promoted by infiltration of circulating macrophages. Monocyte chemoattractant protein-1 (MCP-1) has been shown to attract macrophages in kidney diseases. P2X7 receptors (P2X7R) are highly expressed on macrophages and are essential components of pro-inflammatory signaling in multiple tissues. Here we show that in diabetic patients, renal P2X7R expression is associated with severe mesangial expansion, impaired glomerular filtration (≤40 ml/min/1.73 sq. m.), and increased interstitial fibrosis. P2X7R activation enhanced the release of MCP-1 in human mesangial cells cultured under high glucose conditions. In mice, P2X7R-deficiency prevented glomerular macrophage attraction and collagen IV deposition; however, the more severe interstitial inflammation and fibrosis often seen in human diabetic kidney diseases was not modelled. Finally, we demonstrate that a P2X7R inhibitor (AZ11657312) can reduce renal macrophage accrual following the establishment of hyperglycemia in a model of diabetic nephropathy. Collectively these data suggest that P2X7R activation may contribute to the high prevalence of kidney disease found in diabetics

The effect of renal denervation on T cells in patients with resistant hypertension

(1) BACKGROUND: Sympathetic overactivity is a major contributor to resistant hypertension (RH). According to animal studies, sympathetic overactivity increases immune responses, thereby aggravating hypertension and cardiovascular outcomes. Renal denervation (RDN) reduces sympathetic nerve activity in RH. Here, we investigate the effect of RDN on T-cell signatures in RH. (2) METHODS: Systemic inflammation and T-cell subsets were analyzed in 17 healthy individuals and 30 patients with RH at baseline and 6 months after RDN. (3) RESULTS: The patients with RH demonstrated higher levels of pro-inflammatory cytokines and higher frequencies of CD4+ effector memory (TEM), CD4+ effector memory residential (TEMRA) and CD8+ central memory (TCM) cells than the controls. After RDN, systolic automated office blood pressure (BP) decreased by -17.6 ± 18.9 mmHg. Greater BP reductions were associated with higher CD4+ TEM (r -0.421, p = 0.02) and CD8+ TCM (r -0.424, p = 0.02) frequencies at baseline. The RDN responders, that is, the patients with ≥10mmHg systolic BP reduction, showed reduced pro-inflammatory cytokine levels, whereas the non-responders had unchanged inflammatory activity and higher CD8+ TEMRA frequencies with increased cellular cytokine production. (4) CONCLUSIONS: The pro-inflammatory state of patients with RH is characterized by altered T-cell signatures, especially in non-responders. A detailed analysis of T cells might be useful in selecting patients for RDN

Sympatho-renal axis in chronic disease

Essential hypertension, insulin resistance, heart failure, congestion, diuretic resistance, and functional renal disease are all characterized by excessive central sympathetic drive. The contribution of the kidney’s somatic afferent nerves, as an underlying cause of elevated central sympathetic drive, and the consequences of excessive efferent sympathetic signals to the kidney itself, as well as other organs, identify the renal sympathetic nerves as a uniquely logical therapeutic target for diseases linked by excessive central sympathetic drive. Clinical studies of renal denervation in patients with resistant hypertension using an endovascular radiofrequency ablation methodology have exposed the sympathetic link between these conditions. Renal denervation could be expected to simultaneously affect blood pressure, insulin resistance, sleep disorders, congestion in heart failure, cardiorenal syndrome and diuretic resistance. The striking epidemiologic evidence for coexistence of these disorders suggests common causal pathways. Chronic activation of the sympathetic nervous system has been associated with components of the metabolic syndrome, such as blood pressure elevation, obesity, dyslipidemia, and impaired fasting glucose with hyperinsulinemia. Over 50% of patients with essential hypertension are hyperinsulinemic, regardless of whether they are untreated or in a stable program of treatment. Insulin resistance is related to sympathetic drive via a bidirectional mechanism. In this manuscript, we review the data that suggests that selective impairment of renal somatic afferent and sympathetic efferent nerves in patients with resistant hypertension both reduces markers of central sympathetic drive and favorably impacts diseases linked through central sympathetics—insulin resistance, heart failure, congestion, diuretic resistance, and cardiorenal disorders

Is the inflammasome a potential therapeutic target in renal disease?

The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury. Pattern recognition receptors that are either membrane bound or cytoplasmic trigger inflammasome assembly. These receptors sense danger signals including damage-associated molecular patterns and pathogen-associated molecular patterns (DAMPS and PAMPS respectively). The best-characterized inflammasome is the NLRP3 inflammasome. On assembly of the NLRP3 inflammasome, post-translational processing and secretion of pro-inflammatory cytokines IL-1β and IL-18 occurs; in addition, cell death may be mediated via caspase-1. Intrinsic renal cells express components of the inflammasome pathway. This is most prominent in tubular epithelial cells and, to a lesser degree, in glomeruli. Several primary renal diseases and systemic diseases affecting the kidney are associated with NLRP3 inflammasome/IL-1β/IL-18 axis activation. Most of the disorders studied have been acute inflammatory diseases. The disease spectrum includes ureteric obstruction, ischaemia reperfusion injury, glomerulonephritis, sepsis, hypoxia, glycerol-induced renal failure, and crystal nephropathy. In addition to mediating renal disease, the IL-1/ IL-18 axis may also be responsible for development of CKD itself and its related complications, including vascular calcification and sepsis. Experimental models using genetic deletions and/or receptor antagonists/antiserum against the NLRP3 inflammasome pathway have shown decreased severity of disease. As such, the inflammasome is an attractive potential therapeutic target in a variety of renal diseases

Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension Durability of Blood Pressure Reduction Out to 24 Months

Renal sympathetic hyperactivity is seminal in the maintenance and progression of hypertension. Catheter-based renal sympathetic denervation has been shown to significantly reduce blood pressure (BP) in patients with hypertension. Durability of effect beyond 1 year using this novel technique has never been reported. A cohort of 45 patients with resistant hypertension (systolic BP GT = 160 mm Hg on GT = 3 antihypertension drugs, including a diuretic) has been originally published. Herein, we report longer-term follow-up data on these and a larger group of similar patients subsequently treated with catheter-based renal denervation in a nonrandomized manner. We treated 153 patients with catheter-based renal sympathetic denervation at 19 centers in Australia, Europe, and the United States. Mean age was 57 +/- 11 years, 39% were women, 31% were diabetic, and 22% had coronary artery disease. Baseline values included mean office BP of 176/98 +/- 17/15 mm Hg, mean of 5 antihypertension medications, and an estimated glomerular filtration rate of 83 +/- 20 mL/min per 1.73 m(2). The median time from first to last radiofrequency energy ablation was 38 minutes. The procedure was without complication in 97% of patients (149 of 153). The 4 acute procedural complications included 3 groin pseudoaneurysms and 1 renal artery dissection, all managed without further sequelae. Postprocedure office BPs were reduced by 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg at 1, 3, 6, 12, 18, and 24 months, respectively. In conclusion, in patients with resistant hypertension, catheter-based renal sympathetic denervation results in a substantial reduction in BP sustained out to GT = 2 years of follow-up, without significant adverse events. (Hypertension. 2011;57:911-917.