CRRL269
| Autor: | Seethalakshmi R. Iyer, Tomoko Ichiki, Ye Zheng, Gail J. Harty, Xiao Li Wang, Shinobu Sugihara, John C. Burnett, Hon Chi Lee, Joseph P. Grande, Yang Chen, S. Jeson Sangaralingham |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Physiology medicine.drug_class 030232 urology & nephrology Natriuresis Peptide Apoptosis Blood Pressure Cardiorenal syndrome 030204 cardiovascular system & hematology Pharmacology urologic and male genital diseases Renal Agents Article Renal Circulation 03 medical and health sciences 0302 clinical medicine Dogs Natriuretic peptide medicine Humans Animals Receptor Natriuretic Peptides Cyclic GMP chemistry.chemical_classification urogenital system Activator (genetics) business.industry Angiotensin II Acute kidney injury Natriuretic Peptide C-Type Acute Kidney Injury medicine.disease Diuresis chemistry Heart failure Hypotension Cardiology and Cardiovascular Medicine business Receptors Atrial Natriuretic Factor Atrial Natriuretic Factor Biomarkers Glomerular Filtration Rate |
| Zdroj: | Circ Res |
| ISSN: | 1524-4571 |
| Popis: | Rationale: Acute kidney injury (AKI) has a high prevalence and mortality in critically ill patients. It is also a powerful risk factor for heart failure incidence driven by hemodynamic changes and neurohormonal activation. However, no drugs have been approved by the Food and Drug Administration. Endogenous pGC-A (particulate guanylyl cyclase A receptor) activators were reported to preserve renal function and improve mortality in AKI patients, although hypotension accompanied by pGC-A activators have limited their therapeutic potential. Objective: We investigated the therapeutic potential of a nonhypotensive pGC-A activator/designer natriuretic peptide, CRRL269, in a short-term, large animal model of ischemia-induced AKI and also investigated the potential of uCNP (urinary C-type natriuretic peptide) as a biomarker for AKI. Methods and Results: We first showed that CRRL269 stimulated cGMP generation, suppressed plasma angiotensin II, and reduced cardiac filling pressures without lowering blood pressure in the AKI canine model. We also demonstrated that CRRL269 preserved glomerular filtration rate, increased renal blood flow, and promoted diuresis and natriuresis. Further, CRRL269 reduced kidney injury and apoptosis as evidenced by ex vivo histology and tissue apoptosis analysis. We also showed, compared with native pGC-A activators, that CRRL269 is a more potent inhibitor of apoptosis in renal cells and induced less decreases in intracellular Ca 2+ concentration in vascular smooth muscle cells. The renal antiapoptotic effects were at least mediated by cGMP/PKG pathway. Further, CRRL269 inhibited proapoptotic genes expression using a polymerase chain reaction gene array. Additionally, we demonstrated that AKI increased uCNP levels. Conclusions: Our study supports developing CRRL269 as a novel renocardiac protective agent for AKI treatment. |
| Databáze: | OpenAIRE |
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