Klotho relieves inflammation and exerts a cardioprotective effect during renal ischemia/reperfusion-induced cardiorenal syndrome

Author(s)

Cruz Junho, Carolina Victoria ; Gonzalez-Lafuente, Laura ; Silva Neres-Santos, Raquel ; Alberto Navarro-Garcia, Jose ; Rodriguez-Sanchez, Elena ; Ruiz-Hurtado, Gema ; Sorelli Carneiro-Ramos, Marcela

• Document type: Journal article
• Source: BIOMEDICINE & PHARMACOTHERAPY; v. 153, p. 13-pg., 2022-08-09.

Abstract

Background: Renal ischemia and reperfusion injury (IRI) is the main cause of acute kidney injury (AKI). AKI induces the development of cardiac hypertrophy (CH) during cardiorenal syndrome (CRS), and cardiomyocyte calcium mishandling though systemic inflammation after 8 days of renal IRI. Klotho has recently been described as an anti-inflammatory component. Given this, Klotho treatment could prevent or attenuate the inflammation, thereby also preventing electrical cardiac outcomes incurred by CRS. The aim of this study was to investigate the therapeutic role of Klotho in CRS after unilateral renal IRI through its anti-inflammatory action.Methods: We examined renal tissue structure and function, intracellular Ca2+ dynamics in adult ventricular cardiomyocytes and serum cytokine levels from C57BL/6 mice that suffered unilateral renal IRI by occluding the left pedicle for 60 min and reperfusion for 8 days. The animals were treated with recombinant Klotho protein starting from the day of the surgery, then daily for 8 days.Results: After Klotho treatment for 8 days, the left renal tissue remained damaged, however the renal function was restored due to the right kidney tissue preservation. In parallel, Klotho also prevented an increase in serum interleukin (IL-) 6, IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) levels. CH and low cell contraction were also prevented, as well as a decrease in systolic Ca2+ transients and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity measured as Ca2+ transient decay, an increase in spontaneous Ca2+ release and the incidence of pro-arrhythmic events.Conclusions: The Klotho treatment showed promise, playing an important role in the pathophysiology of CRS. We were unable to observe a total renoprotective role of the compound in the model; in turn, a cardioprotective role of Klotho was demonstrated through the prevention of hypertrophy and normalization of the Ca2+ cycle dysfunction of cardiomyocytes. We propose that Klotho acts in the cardiorenal syndrome by systematically preventing inflammation and increased FGF23, alleviating cardiac outcomes. (AU)

• FAPESP's process: 18/19204-9 - Effects of the silencing and super-expressing of Klotho gene in cardiac function through hypertrophy induced by cardiorenal syndrome
• Grantee: Carolina Victória da Cruz Junho
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 15/19107-5 - TLR4 and complement system : possible key mechanism in renal ischemia/reperfusion induced cardiac hypertrophy
• Grantee: Marcela Sorelli Carneiro Ramos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/03089-6 - Role of the Klotho/FGF23 axis in the development of Type 3 Cardiorenal Syndrome induced by ischemic renal injury
• Grantee: Carolina Victória da Cruz Junho
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/11077-0 - Cardiac alterations induced by renal inflammation models: participation of the Klotho/FGF-23 axis
• Grantee: Marcela Sorelli Carneiro Ramos
• Support Opportunities: Regular Research Grants