CRRL269

Circ Res. 2019 May 10;124(10):1462-1472. doi: 10.1161/CIRCRESAHA.118.314164.

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.

Keywords: acute kidney injury; apoptosis; cardiorenal syndrome; heart failure; natriuretic peptide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / prevention & control
  • Acute Kidney Injury / urine*
  • Angiotensin II / blood
  • Animals
  • Apoptosis / drug effects
  • Biomarkers / urine
  • Blood Pressure / physiology
  • Cyclic GMP / biosynthesis
  • Diuresis / drug effects
  • Dogs
  • Glomerular Filtration Rate / drug effects
  • Male
  • Natriuresis / drug effects
  • Natriuretic Peptide, C-Type / urine*
  • Natriuretic Peptides / pharmacology
  • Natriuretic Peptides / therapeutic use*
  • Receptors, Atrial Natriuretic Factor / analysis
  • Receptors, Atrial Natriuretic Factor / drug effects
  • Renal Agents / therapeutic use*
  • Renal Circulation / drug effects

Substances

  • Biomarkers
  • CRRL269
  • Natriuretic Peptides
  • Renal Agents
  • Angiotensin II
  • Natriuretic Peptide, C-Type
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor A
  • Cyclic GMP