sncRNA levels predict SNORD105B is a novel biomarker of chronic kidney disease risk and SGLT2 inhibitor response in type 2 diabetes

Abstract

Chronic kidney disease (CKD) is a common complication of type 2 diabetes, characterized by reduced kidney function and/or albuminuria, yet its progression varies widely among individuals. While sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to protect against kidney decline, the molecular mechanisms underlying their renoprotective effects remain incompletely understood. Circulating small non-coding RNAs (sncRNAs), particularly microRNAs, have been linked to CKD but the contribution of other sncRNA classes is less explored. We profiled plasma sncRNAs in 263 participants with type 2 diabetes from the Hoorn DCS cohort without CKD at baseline, followed for ∼9 years ( n control = 122, n case = 141). sncRNA profiling was also performed before and after treatment of SGLT2 inhibitors in three trials ( n = 65, total) to assess drug-induced molecular changes in the circulation. Eleven sncRNAs were nominally associated with incident CKD, most strongly SNORD12C and SNORD105B . In an independent SGLT2 inhibitor trial, exploratory analyses identified 34 sncRNAs that changed following treatment, including SNORD105B . Preliminary analyses linked these snoRNAs to co-regulated proteins, suggesting potential functional relevance. Our results identify snoRNAs, particularly SNORD105B , as potential novel markers of CKD risk and SGLT2 inhibitor response in type 2 diabetes, revealing an unexplored sncRNA axis and providing a foundation for future functional studies into their mechanistic role in CKD progression.