Impaired adiponectin pathway in obesity-induced CKD: focus on gender differences

Chronic kidney disease (CKD) is a major and increasing public health issue affecting more than 10% of the global population. Besides, the prevalence of obesity has increased dramatically during the past decades, which has been a major health problem. An increasing number of studies find obesity as a driver of CKD progression.
In this context, our group has developed an expertise in stress-induced metabolic adaptations of proximal tubular epithelial cells (PTEC). We demonstrated that obesity-induced CKD led to a disturbance of lipid metabolism along with mitochondrial (mt) dysfunction in these cells. Notably, in a context of obesity-induced CKD, we showed that ceramides (Cer) were increased in kidney in obese male mice but not in female mice (Juszczak et al. 2023). Cer is clearly associated with renal inflammation, mt dysfunction, and insulin resistance. Interestingly, AMP-activated protein kinase (AMPK)-adiponectin (APN) axis in obese female mice appeared conserved. Indeed, their renal tissues presented higher mRNA and protein levels of APN receptors that may explain why they were protected from Cer accumulation. Furthermore, APN KO mice showed a decline in renal function at 4 months of age compared to wild type (Fig. 1A-B). We also highlighted accumulation of vacuoles in PTEC in APN KO mice aged of 4 months compared to their WT littermates (Fig. 1C). This change was further aggravated with High-Fat Diet (HFD). Moreover, a link between APN axis and Cer metabolism has also been highlighted in adipocytes and hepatocytes in a setting of obesity, demonstrating a beneficial effect of APN through the activation of ceramidases, improving mt and lipid metabolisms.
Notably, such disturbances in lipid metabolism are also observed in senescence. Indeed, increased lipid species such as Cer and sphingosine have been particularly linked to senescence state. Besides, another group recently showed that aged APN KO mice (20 months) presented tubulo-interstitial and periglomerular fibrosis, increased inflammatory markers and shortened lifespan.
In view of these considerations, we assume that ageing leads to an APN pathway disturbance in the kidneys. Given the role of APN in cell metabolism homeostasis, such deregulation may influence the disturbances in lipid metabolism during senescence in PTEC and impact the SASP secretome, favoring a senescent environment. Therefore, modulating the APN axis is an interesting approach to better understand the mechanisms underlying renal senescence. Altogether, APN axis could promote protective effect against Cer accumulation and its deleterious cellular impact toward a senescent phenotype.