Bridging gut microbiota and renal health: Klotho as a promising therapeutic agent in DKD

Diabetic kidney disease (DKD) remains a serious microvascular consequence of diabetes mellitus globally. DKD pathophysiology is complex and multifactorial; while current therapies are limited, they offer partial renoprotection. However, disease progression continues, underscoring the need for novel therapeutic avenues. Recent advances highlight the "gut-kidney axis" as a pivotal contributor to DKD. Hyperglycemia-induced gut dysbiosis exacerbates renal injury through increased systemic inflammation, RAAS activation, and buildup of uremic toxins. These toxins epigenetically suppress renal expression of α-Klotho, an anti-aging protein with critical antioxidative, anti-inflammatory, and antifibrotic functions, thereby accelerating DKD progression. Despite its emerging importance, α-Klotho remains underexplored as a therapeutic target in DKD, particularly in gut microbiota regulation. α-Klotho could be a potential therapeutic target against DKD via gut-kidney axis modulation. This review elucidates the mechanistic link between gut dysbiosis and the progression of DKD. Additionally, it highlights the impact of uremic toxins on renal α-Klotho expression and subsequent progression to DKD. Therefore, we proposed α-Klotho as a potential therapeutic avenue against DKD through modulation of the gut-kidney axis. This review also highlighted that the combination therapy approach may offer synergistic benefits by targeting multiple pathogenic pathways.