Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Protects Against Acute Kidney Injury-Mediated Chronic Kidney Disease: Role of Oxidative Stress.
Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR consequences; however, the potential benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone has to be further explored. In this study, we evaluated the efficacy of finerenone to prevent the acute and chronic consequences of ischemic acute kidney injury. For the acute study (24 hours), 18 rats were divided into sham, bilateral renal ischemia of 25 minutes, and rats that received 3 doses of finerenone at 48, 24, and 1 hour before the ischemia. For the chronic study (4 months), 23 rats were divided into sham, rats that underwent 45 minutes of bilateral ischemia, and rats treated with finerenone at days 2 and 1 and 1 hour before IR. We found that after 24 hours of reperfusion, the untreated IR rats presented kidney dysfunction and tubular injury. Kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin mRNA levels were increased. In contrast, the rats treated with finerenone displayed normal kidney function and significantly lesser tubular injury and kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin levels. After 4 months, the IR rats developed chronic kidney disease, evidenced by kidney dysfunction, increased proteinuria and renal vascular resistance, tubular dilation, extensive tubule-interstitial fibrosis, and an increase in kidney transforming growth factor-β and collagen-I mRNA. The transition from acute kidney injury to chronic kidney disease was fully prevented by finerenone. Altogether, our data show that in the rat, finerenone is able to prevent acute kidney injury induced by IR and the chronic and progressive deterioration of kidney function and structure.
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.).
Lionel
L
Lattenist
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.).
Sebastian M
SM
Lechner
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.).
Smail
S
Messaoudi
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.).
Alan
A
Le Mercier
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.).
Soumaya
S
El Moghrabi
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.).
Sonia
S
Prince
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.).
Norma A
NA
Bobadilla
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.).
Peter
P
Kolkhof
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.). frederic.jaisser@inserm.fr.
Frédéric
F
Jaisser
From the INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, France (L.L., S.M.L., S.M., A.L.M., S.E.M., S.P., F.J., J.B.-C.); Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México and Nephrology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (N.A.B., J.B.-C.); BAYER AG, Cardiology Research, Wuppertal, Germany (P.K.); and INSERM, CIC1433, CHRU de Nancy, F-CRIN INI-CRCT Network, France (F.J.).
Jonatan
J
Barrera-Chimal
D058186:Acute Kidney Injury / Q000150:complications / Q000378:metabolism*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004195:Disease Models, Animal; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D000071068:Lipocalin-2 / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D009287:Naphthyridines / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D000071068:Lipocalin-2; D008315:Malondialdehyde; D000451:Mineralocorticoid Receptor Antagonists; D009287:Naphthyridines; C110936:Havcr1 protein, rat; C576501:finerenone
endothelin receptors; fibrosis; ischemia; renal circulation; reperfusion