This study evaluated the expression of the long non-coding RNA SNHG12, microRNA miR-129-5p, and the cytokine receptor subunit IL6ST in human subjects and investigated their relationships with diabetic nephropathy (DN). The clinical sample comprised 150 patients with type 2 diabetes mellitus (T2DM) and 150 patients diagnosed with DN. Target gene expression in patient samples was measured using reverse transcription quantitative real-time PCR (RT-qPCR).
In the DN patient group, SNHG12 and IL6ST were significantly upregulated relative to controls, while miR-129-5p was downregulated. Multivariate regression analysis performed by the authors identified elevated SNHG12 as a risk factor associated with DN. Based on these clinical observations, the authors proposed that SNHG12 could serve as a potential auxiliary diagnostic biomarker for DN.
To model diabetic kidney injury in vitro, the investigators used human proximal tubular epithelial HK-2 cells exposed to high glucose (HG) conditions. Experimental endpoints and assays included:
These methods were used to test the functional consequences of manipulating SNHG12 expression in the HG-treated HK-2 cells and to probe direct molecular interactions.
Under HG conditions, silencing of SNHG12 produced several cellular effects consistent with reduced injury in the HK-2 model. Specifically, SNHG12 knockdown:
Together, these results indicate that reducing SNHG12 expression in HG-exposed tubular epithelial cells mitigates key pathophysiologic processes implicated in DN: impaired cell survival, inflammation, and fibrotic activation.
Mechanistic experiments established a regulatory axis linking SNHG12, miR-129-5p, and IL6ST. The authors report that SNHG12 can directly bind to and regulate miR-129-5p, functioning as a competing endogenous RNA (ceRNA) or molecular sponge. In turn, miR-129-5p targets the 3' untranslated region (3'UTR) of IL6ST, the interleukin-6 signal transducer (also known as gp130 in related literature), thereby regulating IL6ST expression.
These interactions were supported by RIP assays and dual-luciferase reporter experiments described in the study, which indicate direct binding and regulatory relationships between the lncRNA, the microRNA, and the IL6ST transcript.
To validate the functional significance of the SNHG12 — miR-129-5p — IL6ST axis, the investigators performed rescue experiments in HG-treated HK-2 cells. They report that either inhibition of miR-129-5p or overexpression of IL6ST partially reversed the protective cellular effects induced by SNHG12 knockdown. Specifically, these interventions attenuated SNHG12 knockdown–associated increases in proliferation and reductions in apoptosis, inflammation, and fibrosis markers.
These partial reversals indicate that the protective effect of lowering SNHG12 involves, at least in part, restoration of miR-129-5p suppression and consequent modulation of IL6ST. The data support a model in which SNHG12 promotes DN-relevant cellular dysfunction by sponging miR-129-5p, leading to higher IL6ST expression and downstream pro-inflammatory or pro-fibrotic signaling.
The authors conclude that SNHG12 promotes the progression of diabetic nephropathy by upregulating IL6ST expression through sponging of miR-129-5p. Clinically, the observed upregulation of SNHG12 and IL6ST and downregulation of miR-129-5p in DN patients suggest SNHG12 may have potential utility as an auxiliary diagnostic biomarker for DN. The in vitro functional data indicate that targeting SNHG12 or modulating the miR-129-5p/IL6ST axis could be explored in future studies as a therapeutic strategy, although translational steps were not addressed in this report.
Ethics approval for the clinical components of the study was obtained from the Ethics Committee of Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, and all participants provided written informed consent. The authors declared no competing interests. Where the source did not provide additional experimental detail or in vivo validation, those specifics were not reported in the article.