Reciprocal regulation between the molecular clock and kidney injury

Abstract

Molecular clock; Kidney injury

Rellotge molecular; Lesió renal

Reloj molecular; Lesión renal

Tubulointerstitial fibrosis is the common pathological substrate for many etiologies leading to chronic kidney disease. Although perturbations in the circadian rhythm have been associated with renal disease, the role of the molecular clock in the pathogenesis of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (unilateral ureteral obstruction, folic acid, and adenine nephrotoxicity), using genetically modified mice with selective deficiencies of the clock components Bmal1, Clock, and Cry. We found that the molecular clock pathway was enriched in damaged tubular epithelial cells with marked metabolic alterations. In human tubular epithelial cells, TGFβ significantly altered the expression of clock components. Although Clock played a role in the macrophage-mediated inflammatory response, the combined absence of Cry1 and Cry2 was critical for the recruitment of neutrophils, correlating with a worsening of fibrosis and with a major shift in the expression of metabolism-related genes. These results support that renal damage disrupts the kidney peripheral molecular clock, which in turn promotes metabolic derangement linked to inflammatory and fibrotic responses.

This work was supported by grants from the Ministerio de Ciencia e Innovación PID2019-104233RB-100/AEI/10.13039/501100011033 (S Lamas), Instituto de Salud Carlos III REDinREN RD12/0021/0009 and RD16/0009/0016 (S Lamas), Comunidad de Madrid “NOVELREN” B2017/BMD-3751 and INNOREN P2022/BMD-7221 (S Lamas and C Barbas), and Fundación Renal “Iñigo Alvarez de Toledo” (S Lamas), all from Spain. C Rey-Serra has been the recipient of an FPI research training contract from the Spanish Research State Agency (BES-2016-076735). The CBMSO receives institutional support from Fundación “Ramón Areces.” We acknowledge the laboratories of Fernando Rodríguez Pascual (CBMSO) for helping with plasmid constructions and of Marta Ruiz‐Ortega at the Fundación Jiménez Díaz for helping with immunohistochemistry. We also acknowledge the help of the following facilities of the CBMSO: animal housing, flow cytometry, and confocal and electron microscopy.