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. 2020 Dec;20(12):3451-3461.
doi: 10.1111/ajt.15961. Epub 2020 Jun 2.

Diabetic nephropathy alters circulating long noncoding RNA levels that normalize following simultaneous pancreas-kidney transplantation

Koen E Groeneweg  1 , Yu Wah Au  1 , Jacques M G J Duijs  1 , Barend W Florijn  1 , Cees van Kooten  1 , Johan W de Fijter  1 , Marlies E J Reinders  1 , Anton Jan van Zonneveld  1 , Roel Bijkerk  1
Affiliations

Diabetic nephropathy alters circulating long noncoding RNA levels that normalize following simultaneous pancreas-kidney transplantation

Koen E Groeneweg et al. Am J Transplant. 2020 Dec.

Abstract

Simultaneous pancreas-kidney transplantation (SPKT) replaces kidney function and restores endogenous insulin secretion in patients with diabetic nephropathy (DN). Here, we aimed to identify circulating long noncoding RNAs (lncRNAs) that are associated with DN and vascular injury in the context of SPKT. Based on a pilot study and a literature-based selection of vascular injury-related lncRNAs, we assessed 9 candidate lncRNAs in plasma samples of patients with diabetes mellitus with a kidney function >35 mL/min/1.73 m2 (DM; n = 12), DN (n = 14), SPKT (n = 35), healthy controls (n = 15), and renal transplant recipients (KTx; n = 13). DN patients were also studied longitudinally before and 1, 6, and 12 months after SPKT. Of 9 selected lncRNAs, we found MALAT1, LIPCAR, and LNC-EPHA6 to be higher in DN compared with healthy controls. SPKT caused MALAT1, LIPCAR, and LNC-EPHA6 to normalize to levels of healthy controls, which was confirmed in the longitudinal study. In addition, we observed a strong association between MALAT1, LNC-EPHA6, and LIPCAR and vascular injury marker soluble thrombomodulin and a subset of angiogenic microRNAs (miR-27a, miR-130b, miR-152, and miR-340). We conclude that specific circulating lncRNAs associate with DN-related vascular injury and normalize after SPKT, suggesting that lncRNAs may provide a promising novel monitoring strategy for vascular integrity in the context of SPKT.

Keywords: clinical research/practice; diabetes: secondary complications; molecular biology; pancreas/simultaneous pancreas-kidney transplantation; translational research/science.

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Conflict of interest statement

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Figures

Figure 1
Figure 1
Identification of candidate lncRNAs that associate with diabetic nephropathy. A, Schematic overview of identification strategy of candidate lncRNAs, based on a pilot profiling study in plasma of 6 healthy controls (HC) and 6 diabetic nephropathy (DN) patients, as well as a literature‐based selection of lncRNAs that have been described to associate with vascular injury. B, Scatterplot visualizing differential lncRNA expression between indicated conditions. The red and the green points in the plot represents the statistically significant up and downregulated lncRNAs, respectively, in DN compared with HC. C, Hierarchical clustering shows a distinguishable lncRNA expression profiling among patient plasma samples, visualized in a heatmap. Red depicts high expression; green, low expression [Color figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
Circulating lncRNA levels are affected by diabetic nephropathy and simultaneous pancreas–kidney transplantation. Relative expression of MALAT1 (A), LNC‐EPHA6 (B), LNC‐RPS24 (C), and LIPCAR (D) in the cross‐sectional cohort; healthy controls (HC; n = 15), diabetes mellitus with eGFR > 35 mL/min/1.73 m2 (DM; n = 12), diabetic nephropathy (DN; n = 14), simultaneous pancreas–kidney transplantation (SPKT; n = 35), and kidney transplantation (KTx; n = 13). lncRNA relative expression levels are depicted as logarithmic values. Data are represented as mean ± SD, *P < .05, **P < .01, ***P < .001
Figure 3
Figure 3
Longitudinal study validates differential lncRNA expression and indicates dynamics. Relative expression of MALAT1 (A), LNC‐EPHA6 (B), LNC‐RPS24 (C), and LIPCAR (D) before (D0) and 1, 6, and 12 months (M1, M6, and M12, respectively) after simultaneous pancreas–kidney transplantation. lncRNA relative expression levels are depicted as logarithmic values. eGFR (E) improves after transplantation, and HbA1c (F) declines to steady levels. Data are represented as mean ± SD, *P < .05, ***P < .001
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