Transcriptome-Based Analysis of Kidney Gene Expression Changes Associated with Diabetes in OVE26 Mice, in the Presence and Absence of Losartan Treatment

Abstract

Diabetes is among the most common causes of end-stage renal disease, although its pathophysiology is incompletely understood. We performed next-generation sequencing-based transcriptome analysis of renal gene expression changes in the OVE26 murine model of diabetes (age 15 weeks), relative to non-diabetic control, in the presence and absence of short-term (seven-day) treatment with the angiotensin receptor blocker, losartan (n = 3–6 biological replicates per condition). We detected 1438 statistically significant changes in gene expression across conditions. Of the 638 genes dysregulated in diabetes relative to the non-diabetic state, >70% were downregulation events. Unbiased functional annotation of genes up- and down-regulated by diabetes strongly associated (p<1×10−8) with terms for oxidative stress and for endoplasmic reticulum stress/protein folding. Most of the individual gene products up- or down-regulated with diabetes were unaffected by losartan treatment; however, of the gene products dysregulated in diabetes and influenced by losartan treatment, the vast majority of changes were in the direction of amelioration rather than exacerbation of the diabetic dysregulation. This group of losartan-protected genes associated strongly with annotation terms for endoplasmic reticulum stress, heat shock proteins, and chaperone function, but not oxidative stress; therefore, the losartan-unaffected genes suggest avenues for additional therapeutic opportunity in diabetes. Interestingly, the gene product most highly upregulated by diabetes (>52-fold), encoded by the cationic amino acid transporter Slc7a12, and the gene product most highly downregulated by diabetes (>99%) – encoded by the “pseudogene” Gm6300 – are adjacent in the murine genome, are members of the SLC7 gene family, and are likely paralogous. Therefore, diabetes activates a near-total genetic switch between these two paralogs. Other individual-level changes in gene expression are potentially relevant to diabetic pathophysiology, and novel pathways are suggested. Genes unaffected by diabetes alone but exhibiting increased renal expression with losartan produced a signature consistent with malignant potential.

Comparative genotypic and phenotypic analysis of human peripheral blood monocytes and surrogate monocyte-like cell lines commonly used in metabolic disease research

“…However, IDO1 was not expressed in any immortalised cell line even following PMA treatment. As IDO1 is involved in tryptophan metabolism and production of kynureninase [ 37 ], its absence suggests that the immortalised cell lines may not be suitable for the study of these immunoregulatory pathways.…”

Differential effects of minocycline on microvascular complications in murine models of type 1 and type 2 diabetes

“…Multiple studies identify inflammation, oxidative stress, apoptosis, and dysregulated immunity and energy metabolism as consistent features in nerve, retinal, and kidney tissue in both mouse models and patients with T1D and T2D [3][4][5][6][24][25][26][27][28][29][30][31][32]. We and others [8][9][10][11][12][13][33][34][35][36] have consequently investigated minocycline, with its anti-inflammatory, anti-apoptotic, and anti-oxidant effects [7], as a possible therapeutic agent in DPN, DR, and DKD.…”

Rat mRNA expression profiles associated with inhibition of ischemic acute kidney injury by losartan

“…Next-generation deep sequencing was used in the present study to compare the mRNA expression profiles between the rat kidney tissues from different groups, as previously described with minor modifications [17]. Briefly, total RNA samples from collected rat kidney tissues were extracted using TRIzol solution (Thermo Fisher Scientific, MA, U.S.A.), in accordance with the manufacturer’s instructions.…”

“…In addition, large-scale gene expression profile analysis also revealed that losartan could induce changes in the expression of a large number of genes while performing its therapeutic functions. In a next-generation sequencing-based transcriptome analysis, more than 1400 genes were identified as being significantly differentially expressed in a murine model of diabetes after treatment with losartan; these were shown to be involved in multiple biological processes (BPs) including endoplasmic reticulum stress and heat shock protein-related signaling [17]. These reports clearly showed that the alterations of key gene expression might be critical mechanisms mediating the various therapeutic effects of losartan, and gene expression profile analysis could be applied as a powerful method for the study of losartan pharmacology.…”