Impact of the circadian regulation on the metabolic basis of kidney fibrosis

Resumo

Renal fibrosis is the consequence of a maintained response to chronic inflammation and the converging pathway for several entities of different origin underlying chronic kidney disease (CKD). Tubuleinterstitial fibrosis is hallmarked by a profound derangement in metabolism, whereby inflammation and mitochondrial dysfunction reciprocally interact, promoting the increased deposition of extracellular matrix (ECM), which replaces the cellular void and leads to suppression of renal function. Perturbations in the circadian rhythm have been shown to pervade every aspect of human pathology, including renal disease. However, the role of the molecular clock in the instauration of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (UUO, FAN and adenine toxicity), employing genetically-modified mice with selective deficiencies of the clock components Bmal1, Clock and Cry. We found that UUO induced a marked increase in the expression of core clock components. In human tubular epithelial cells, the pro-fibrotic mediator, TGFβ, significantly induced the expression of Bmal1. We further observed that the absence of Cry drastically aggravated kidney fibrosis, while both Cry and Clock played a role in the accompanying inflammatory response. Suppression of Cry1/2 was associated with a major shift in the expression of metabolism-related genes, underscoring the importance of metabolic dysfunction in fibrosis. These results support a reciprocal interaction between the circadian clock and the response to kidney injury. The feeding-fasting pattern is an essential external cue for the robustness of the circadian rhythm. Unpredictable eating patterns can disturb the circadian coordination of metabolic and physiological processes, contributing to the development of chronic diseases. Time-restricted feeding (TRF) is an eating intervention that has been described as a beneficial therapy for obesity and metabolic syndromes. Here, we explored the impact of TRF on renal fibrosis in mice fed high-fat diet (HFD) subjected to kidney damage. Our study demonstrates that TRF attenuates the inflammatory and fibrosis responses, by conferring protection from ER stress and metabolic alterations related to kidney damage.