CRRL269

Yang Chen, Gail J. Harty, Ye Zheng, Seethalakshmi R. Iyer, Shinobu Sugihara, S Jeson Sangaralingham, Tomoko Ichiki, Joseph Peter Grande, Hon Chi Lee, Xiaoli Wang, John C Jr. Burnett

Research output: Contribution to journalArticle

Abstract

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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)1462-1472
Number of pages11
JournalCirculation research
Volume124
Issue number10
DOIs
StatePublished - May 10 2019

Fingerprint

Acute Kidney Injury
C-Type Natriuretic Peptide
Kidney
Apoptosis
Protective Agents
Natriuretic Peptides
Natriuresis
Mortality
Renal Circulation
Diuresis
United States Food and Drug Administration
Glomerular Filtration Rate
Vascular Smooth Muscle
Critical Illness
Angiotensin II
Hypotension
Smooth Muscle Myocytes
Canidae
Histology
Therapeutics

Keywords

  • acute kidney injury
  • apoptosis
  • cardiorenal syndrome
  • heart failure
  • natriuretic peptide

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Chen, Y., Harty, G. J., Zheng, Y., Iyer, S. R., Sugihara, S., Sangaralingham, S. J., ... Burnett, J. C. J. (2019). CRRL269. Circulation research, 124(10), 1462-1472. https://doi.org/10.1161/CIRCRESAHA.118.314164

CRRL269. / Chen, Yang; Harty, Gail J.; Zheng, Ye; Iyer, Seethalakshmi R.; Sugihara, Shinobu; Sangaralingham, S Jeson; Ichiki, Tomoko; Grande, Joseph Peter; Lee, Hon Chi; Wang, Xiaoli; Burnett, John C Jr.

In: Circulation research, Vol. 124, No. 10, 10.05.2019, p. 1462-1472.

Research output: Contribution to journalArticle

Chen, Y, Harty, GJ, Zheng, Y, Iyer, SR, Sugihara, S, Sangaralingham, SJ, Ichiki, T, Grande, JP, Lee, HC, Wang, X & Burnett, JCJ 2019, 'CRRL269', Circulation research, vol. 124, no. 10, pp. 1462-1472. https://doi.org/10.1161/CIRCRESAHA.118.314164
Chen Y, Harty GJ, Zheng Y, Iyer SR, Sugihara S, Sangaralingham SJ et al. CRRL269. Circulation research. 2019 May 10;124(10):1462-1472. https://doi.org/10.1161/CIRCRESAHA.118.314164
Chen, Yang ; Harty, Gail J. ; Zheng, Ye ; Iyer, Seethalakshmi R. ; Sugihara, Shinobu ; Sangaralingham, S Jeson ; Ichiki, Tomoko ; Grande, Joseph Peter ; Lee, Hon Chi ; Wang, Xiaoli ; Burnett, John C Jr. / CRRL269. In: Circulation research. 2019 ; Vol. 124, No. 10. pp. 1462-1472.
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AU - Chen, Yang

AU - Harty, Gail J.

AU - Zheng, Ye

AU - Iyer, Seethalakshmi R.

AU - Sugihara, Shinobu

AU - Sangaralingham, S Jeson

AU - Ichiki, Tomoko

AU - Grande, Joseph Peter

AU - Lee, Hon Chi

AU - Wang, Xiaoli

AU - Burnett, John C Jr.

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N2 - 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 Ca2+ 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.

AB - 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 Ca2+ 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.

KW - acute kidney injury

KW - apoptosis

KW - cardiorenal syndrome

KW - heart failure

KW - natriuretic peptide

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