The renalase pathway is a previously unrecognized mechanism for regulating cardiac function and blood pressure. In this pathway, renalase, a novel secreted amine oxidase that is inactive at baseline, ...is rapidly turned on (∼10 fold increase) by either a modest increase in blood pressure or by brief surges in plasma catecholamines. The active enzyme degrades circulating catecholamines, causing a significant fall in blood pressure. Plasma catecholamines not only activate renalase enzymatic activity but also lead to a 3–4 fold stimulation of renalase secretion. The renalase knockout mouse (KO) is hypertensive and exquisitely sensitive to cardiac ischemia. Abnormalities in the renalase pathway are present in animal models of chronic kidney disease (CKD) and hypertension. Two single-nucleotide polymorphisms (SNPs) in the renalase gene were found to be associated with essential hypertension in man. Blood renalase levels are inversely correlated with glomerular filtration rate (GFR) and are markedly reduced in patients with end-stage kidney disease (ESRD). We hypothesize that renalase is secreted into blood by the kidney (although also expressed in heart, skeletal muscle, and small intestine) and plays a key role in regulating blood pressure and cardiovascular function, and that abnormalities in the renalase pathway contribute to the heightened cardiovascular risks observed in patients with CKD.
Cisplatin is an effective chemotherapeutic agent, but significant nephrotoxicity limits its clinical use. Despite extensive investigation of the acute cellular and molecular responses to cisplatin, ...the mechanisms of progression from acute to chronic kidney injury have not been explored. We used functional and morphological metrics to establish a time-point when the transition from acute and reversible kidney injury to chronic and irreparable kidney disease is clearly established. In mice administered 1 or 2 doses of intraperitoneal cisplatin separated by 2 weeks, kidney function returned toward baseline two weeks after the first dose, but failed to return to normal two weeks following a second dose. Multiphoton microscopy revealed increased glomerular epithelial and proximal tubular damage in kidneys exposed to two doses of cisplatin compared with those exposed to a single dose. In contrast, there was no evidence of fibrosis, macrophage invasion, or decrease in endothelial cell mass in chronically diseased kidneys. Pathway analysis of microarray data revealed regulated necrosis as a key determinant in the development of chronic kidney disease after cisplatin administration. Western blot analysis demonstrated activation of proteins involved in necroptosis and increased expression of kidney injury markers, cellular stress response regulators, and upstream activators of regulated necrosis, including Toll-like receptors 2 and 4. These data suggest that unresolved injury and sustained activation of regulated necrosis pathways, rather than fibrosis, promote the progression of cisplatin-induced acute kidney injury to chronic kidney disease.
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An increased risk for developing essential hypertension, stroke and diabetes is associated with single nucleotide gene polymorphisms in renalase, a newly described secreted flavoprotein with ...oxidoreductase activity. Gene deletion causes hypertension, and aggravates acute ischemic kidney (AKI) and cardiac injury. Independent of its intrinsic enzymatic activities, extracellular renalase activates MAPK signaling and prevents acute kidney injury (AKI) in wild type (WT) mice. Therefore, we sought to identity the receptor for extracellular renalase.
RP-220 is a previously identified, 20 amino acids long renalase peptide that is devoid of any intrinsic enzymatic activity, but it is equally effective as full-length recombinant renalase at protecting against toxic and ischemic injury. Using biotin transfer studies with RP-220 in the human proximal tubular cell line HK-2 and protein identification by mass spectrometry, we identified PMCA4b as a renalase binding protein. This previously characterized plasma membrane ATPase is involved in cell signaling and cardiac hypertrophy. Co-immunoprecipitation and co-immunolocalization confirmed protein-protein interaction between endogenous renalase and PMCA4b. Down-regulation of endogenous PMCA4b expression by siRNA transfection, or inhibition of its enzymatic activity by the specific peptide inhibitor caloxin1b each abrogated RP-220 dependent MAPK signaling and cytoprotection. In control studies, these maneuvers had no effect on epidermal growth factor mediated signaling, confirming specificity of the interaction between PMCA4b and renalase.
PMCA4b functions as a renalase receptor, and a key mediator of renalase dependent MAPK signaling.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Repeated administration of cisplatin causes CKD. In previous studies, we reported that the kidney-secreted survival protein renalase (RNLS) and an agonist peptide protected mice from ...cisplatin-induced AKI.
To investigate whether kidney-targeted delivery of RNLS might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a RNLS agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of RNLS, single-cell RNA sequencing analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma RNLS in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy.
In mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney RNLS; genetic deletion of RNLS was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA sequencing analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature and suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma RNLS levels trended lower at day 14 post-treatment.
Kidney-targeted delivery of RNLS agonist RP81-MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.
PURPOSE OF REVIEWRenalase is a secreted amine oxidase that is synthesized in the kidney, and that metabolizes circulating catecholamines. Tissue and plasma renalase levels are decreased in models of ...chronic kidney disease. Recent data indicate that renalase deficiency is associated with increased blood pressure and elevated circulating catecholamines. The mechanisms of hypertension in renalase deficiency and the possibility that renalase regulates the renal dopamine system are discussed.
RECENT FINDINGSCharacterization of the renalase knockout mouse model revealed that renalase deficiency increases SBP and DBP. Renal and cardiac functions are unaffected, but there is evidence of sympathetic activation, with elevation of plasma and urine catecholamines. Renalase is continually excreted in urine, and is enzymatically active and could modulate catecholamines levels in tubular fluid. Renalase expression is modulated by salt intake, and recombinant renalase has a potent and prolonged hypotensive effect on blood pressure in Dahl salt-sensitive rats and rats with chronic kidney disease. Plasma renalase levels are inversely associated with SBP in patients with resistant hypertension. A functional mutation in renalase (Glu37Asp) associated with essential hypertension also predicts more severe cardiac hypertrophy, dysfunction, and ischemia in individuals with stable coronary artery disease, comparable blood pressure and normal renal function.
SUMMARYUrinary renalase metabolizes urinary catecholamines, and perhaps regulates dopamine concentration in luminal fluid, and modulate proximal tubular sodium transport. Renalase deficiency is associated with increased sympathetic tone and resistant hypertension. Recombinant renalase is a potent antihypertensive agent in Dahl salt-sensitive rats and in rats with chronic kidney disease.
While investigating the mechanisms that could mediate the significant burden of cardiovascular complications observed in persons with chronic kidney disease (CKD) and end stage renal disease (ESRD), ...we identified a previously unknown protein, which we named renalase (RNLS). Over the past 15 years, our understanding of the biology, physiology, and pathophysiology of RNLS has matured. Here we aim to highlight that RNLS is a bifunctional protein. It metabolizes intracellular nicotinamide adenine dinucleotide (NADH), modulates mitochondrial function, and protects energy metabolism. When secreted outside the cell, independent of its enzymatic properties, it functions as a signaling molecule that mediates resistance to stressful stimuli and promotes cell and organ survival. RNLS has been shown to modulate the severity of acute injury to the pancreas, liver, kidney, and heart. It also protects against the development of chronic injury, and here we highlight the potential use of exogenous RNLS peptide agonists to prevent cisplatin-mediated CKD (CP-CKD).
Renalase, a recently discovered flavoprotein, which is strongly expressed in the kidney and heart, effectively metabolizes catecholamines. It was discovered during the search to identify proteins ...secreted by the kidney that could help explain the high incidence of cardiovascular disease in patients with chronic kidney disease. Recent advances have led to more detailed knowledge of its biology, structure, enzymatic activity, mechanisms of action, associations with human disease states and potential therapeutic value. In this study, we review these advances with a focus on hypertension and kidney disease.
Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the ...accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Traditional histologic methods are limited in their ability to detect pathologic changes of CKD, of which cisplatin therapy is an important cause. In addition, poor reproducibility of available ...methods has limited analysis of the role of fibrosis in CKD. Highly labor-intensive serial sectioning studies have demonstrated that three-dimensional perspective can reveal useful morphologic information on cisplatin-induced CKD. By applying the new technique of multiphoton microscopy (MPM) with clearing to a new mouse model of cisplatin-induced CKD, we obtained detailed morphologic and collagen reconstructions of millimeter-thick renal sections that provided new insights into pathophysiology. Quantitative analysis revealed that a major long-term cisplatin effect is reduction in the number of cuboidal cells of the glomerular capsule, a change we term the "uncapped glomerulus lesion." Glomerulotubular disconnection was confirmed, but connection remnants between damaged tubules and atubular glomeruli were observed. Reductions in normal glomerular capsules corresponded to reductions in GFR. Mild increases in collagen were noted, but the fibrosis was not spatially correlated with atubular glomeruli. Glomerular volume and number remained unaltered with cisplatin exposure, but cortical tubulointerstitial mass decreased. In conclusion, new observations were made possible by using clearing MPM, demonstrating the utility of this technique for studies of renal disease. This technique should prove valuable for further characterizing the evolution of CKD with cisplatin therapy and of other conditions.
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