A Transcriptome Array-Based Approach to Link SGLT-2 and Intrarenal Complement C5 Synthesis in Diabetic Nephropathy

Abstract

Diabetic nephropathy is a common microvascular complication of diabetes mellitus. It is characterized by progressive chronic kidney disease (CKD) with decline of kidney function by hyperfiltration. On a mechanistic level, activation of the complement system has been implicated in the pathogenesis of diabetic nephropathy. Therefore, here we pursued a transcriptome array-based approach to link intrarenal SGLT-2 and the synthesis of distinct complement components in diabetic nephropathy. Publicly available datasets for SLC5A2 (encoding SGLT-2) and complement system components were extracted specifically from microdissected tubulointerstitial (healthy controls: n = 31, diabetic nephropathy: n = 17) and glomerular compartments (healthy controls: n = 21, diabetic nephropathy: n = 12). First, we compared tubulointerstitial and glomerular log₂SLC5A2 mRNA expression levels and confirmed a predominant synthesis within the tubulointerstitial compartment. Among various complement components and receptors, the only significant finding was a positive association between SLC5A2 and the tubulointerstitial synthesis of the complement component C5 in diabetic nephropathy (p = 0.0109). Finally, intrarenal expression of SLC5A2 was associated predominantly with pathways involved in metabolic processes. Interestingly, intrarenal complement C5 synthesis was also associated with enrichment of metabolic signaling pathways, overlapping with SLC5A2 for "metabolism" and "biological oxidations". These observations could be of relevance in the pathogenesis of diabetic nephropathy and implicate a mechanistic link between SGLT-2 and intrarenal complement synthesis.

Keywords: SGLT-2 inhibitor; complement synthesis; diabetic nephropathy; immunology; innate immunity; metabolic dysregulation.

Figure 1

Predominant tubulointerstitial SLC5A2 expression in healthy controls and diabetic nephropathy. (A) Median-centered log₂ SLC5A2 expression levels in microdissected tubulointerstitial (healthy controls: n = 31, diabetic nephropathy: n = 17) and glomerular compartments (healthy controls: n = 21, diabetic nephropathy: n = 12) are shown by scatter dot plots including mean ± SD. Comparisons of groups were performed using the Mann–Whitney U-test to determine differences in medians (** p < 0.01, **** p < 0.0001). (B) Median-centered log₂ SLC5A2 mRNA expression levels in diabetic nephropathy are shown by scatter dot plots including mean ± SD with group separation for female and male sex. Comparisons of groups were performed using the Mann–Whitney U-test to determine differences in medians (n.s: not significant). (C) Correlations between tubulointerstitial and glomerular SLC5A2 mRNA expression levels and laboratory markers of kidney function in diabetic nephropathy are shown by heatmap reflecting mean values of Spearman’s p; circle size represents significance level.

Figure 2

Intrarenal SLC5A2 expression is associated with tubulointerstitial synthesis of distinct complement components. Correlations between tubulointerstitial SLC5A2 mRNA expression levels and various complement components in healthy controls (n = 31) and diabetic nephropathy (n = 17) are shown by heatmap reflecting mean values of Spearman’s p; circle size represents significance level.

Figure 3

Intrarenal SLC5A2 expression and complement C5 synthesis associated with distinct molecular signatures in diabetic nephropathy. (A) Entities −log₁₀ p values of signaling pathways associated with tubulointerstitial SLC5A2 mRNA expression in diabetic nephropathy are shown. (B) Entities −log₁₀ p values of signaling pathways associated with tubulointerstitial C5 mRNA expression in diabetic nephropathy are shown. (C) Number of signaling pathways associated with either tubulointerstitial SLC5A2, complement C5 mRNA expression, or both in diabetic nephropathy are shown.