Protective effects of <i>Katsuwonus pelamis</i> hydrolysates against renal injury: Val-Lys as a potent renoprotective peptide

Elevated serum uric acid (UA), a hallmark of diet-induced metabolic dysregulation, induces renal inflammation and oxidative stress, progressively leading to irreversible kidney injury (KI). Although <i>Katsuwonus pelamis</i> hydrolysates (KPHs) exhibit UA-lowering activity, their potential renoprotective effects remain unknown. In this work, KPHs ameliorating UA-induced HK-2 cell injury <i>in vitro</i> were first obtained by controlled enzymatic hydrolysis. Among them, KPHs with a high degree of hydrolysis (DH) showed relatively better activity in enhancing antioxidant enzyme activities and inhibiting the release of cytokines. Utilizing a sophisticated amalgamation of peptidomics, multivariate statistical analysis, and the random forest model, we successfully screened 13 potential renoprotective peptides, among which VK (Val-Lys) had the highest abundance in Pap-H (prepared using Papain with a high DH). <i>In vitro</i> results revealed that VK protected UA-induced HK-2 cells from injury through antioxidant defense. <i>In vivo</i> results demonstrated that VK effectively ameliorated pathological renal injury in KI rats, partially restoring kidney function, as evidenced by significant reductions in serum UA and creatinine levels. Network pharmacology analysis of the underlying mechanisms further indicated that VK might exert renoprotective effects by regulating IL-17 and TNF signaling pathways. Remarkably, our study reveals that VK functions as a potent renoprotective peptide, which may partially account for the superior renoprotective efficacy observed in KPHs.