Related Experiment Videos
CRRL269
Yang Chen1,2, Gail J Harty1, Ye Zheng1
1From the Cardiorenal Research Laboratory, Department of Cardiovascular Medicine (Y.C., G.J.H., Y.Z., S.R.I., S.S., S.J.S., T.I., J.C.B.), Mayo Clinic, Rochester, MN.
Insights
A novel drug, CRRL269, shows promise for treating acute kidney injury (AKI) by protecting the heart and kidneys without causing hypotension. This study also identified urinary C-type natriuretic peptide (uCNP) as a potential biomarker for AKI.
Area of Science:
- Nephrology
- Cardiology
- Pharmacology
Background:
- Acute kidney injury (AKI) is prevalent in critically ill patients, increasing heart failure risk.
- Existing treatments for AKI are limited, with no FDA-approved drugs.
- Endogenous particulate guanylyl cyclase A (pGC-A) activators show potential but cause hypotension.
Purpose of the Study:
- To investigate the therapeutic potential of CRRL269, a nonhypotensive pGC-A activator, in a canine model of ischemia-induced AKI.
- To evaluate CRRL269's renocardiac protective effects and its impact on hemodynamic parameters.
- To explore urinary C-type natriuretic peptide (uCNP) as a potential biomarker for AKI.
Main Methods:
- Administered CRRL269 to a canine model of ischemia-induced AKI.
- Measured cGMP generation, plasma angiotensin II, cardiac filling pressures, and blood pressure.
- Assessed glomerular filtration rate, renal blood flow, diuresis, natriuresis, kidney injury, and apoptosis.
- Analyzed intracellular Ca2+ concentration and gene expression related to apoptosis.
Main Results:
- CRRL269 increased cGMP, suppressed angiotensin II, and reduced cardiac filling pressures without lowering blood pressure.
- CRRL269 preserved renal function, enhanced renal blood flow, and promoted diuresis and natriuresis.
- CRRL269 reduced kidney injury and apoptosis, demonstrating potent antiapoptotic effects in renal cells.
- AKI was associated with increased uCNP levels, suggesting its potential as a biomarker.
Conclusions:
- CRRL269 demonstrates significant renocardiac protective effects in an AKI model.
- CRRL269's ability to avoid hypotension makes it a promising therapeutic candidate.
- The study supports the development of CRRL269 as a novel treatment for AKI.
- uCNP may serve as a valuable biomarker for detecting and monitoring AKI.
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.