Partial Genetic Deletion of Klotho Aggravates Cardiac Calcium Mishandling in Acute Kidney Injury

• Published in: International journal of molecular sciences 2023-01, Vol.24 (2), p.1322
• Main Authors: González-Lafuente, Laura, Navarro-García, José Alberto, Valero-Almazán, Ángela, Rodríguez-Sánchez, Elena, Vázquez-Sánchez, Sara, Mercado-García, Elisa, Pineros, Patricia, Poveda, Jonay, Fernández-Velasco, María, Kuro-O, Makoto, Ruilope, Luis M, Ruiz-Hurtado, Gema
• Format: Article
• Language: English
• Subjects: acute kidney injury; Acute Kidney Injury - etiology; Aging; Animals; arrhythmia; Ca2+-transporting ATPase; Caffeine; Calcium (intracellular); Calcium (reticular); Calcium - metabolism; calcium handling; Calcium ions; Calcium signalling; Calcium, Dietary; cardiomyocyte; Cardiomyocytes; cardiorenal syndrome; Cardiovascular diseases; Endoplasmic reticulum; Folic acid; Genotype & phenotype; Glucuronidase - genetics; Glucuronidase - metabolism; Heart; Heart failure; Kidney diseases; Kidneys; klotho; Klotho protein; Mice; Mortality; Myocytes, Cardiac - metabolism; Overdose; Systole; Ventricle
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24021322

Acute kidney injury (AKI) is associated with an elevated risk of cardiovascular major events and mortality. The pathophysiological mechanisms underlying the complex cardiorenal network interaction remain unresolved. It is known that the presence of AKI and its evolution are significantly associated with an alteration in the anti-aging factor klotho expression. However, it is unknown whether a klotho deficiency might aggravate cardiac damage after AKI. We examined intracellular calcium (Ca ) handling in native ventricular isolated cardiomyocytes from wild-type (+/+) and heterozygous hypomorphic mice for the klotho gene (+/ ) in which an overdose of folic acid was administered to induce AKI. Twenty-four hours after AKI induction, cardiomyocyte contraction was decreased in mice with the partial deletion of klotho expression (heterozygous hypomorphic klotho named ). This was accompanied by alterations in Ca transients during systole and an impairment of sarco/endoplasmic reticulum Ca -ATPase (SERCA2a) function in mice after AKI induction. Moreover, Ca spark frequency and the incidence of Ca pro-arrhythmic events were greater in cardiomyocytes from heterozygous hypomorphic klotho compared to wild-type mice after AKI. A decrease in klotho expression plays a role in cardiorenal damage aggravating cardiac Ca mishandling after an AKI, providing the basis for future targeted approaches directed to control klotho expression as novel therapeutic strategies to reduce the cardiac burden that affects AKI patients.