Abstract
Aims/hypothesisWe investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes.MethodsAdult male Akita transgenic (Tg) mice overexpressing specifically hnRNP F in their renal proximal tubular cells (RPTCs) were studied. Non-Akita littermates and Akita mice served as controls. Immortalised rat RPTCs stably transfected with plasmid containing either rat Hnrnpf cDNA or rat Ace-2 gene promoter were also studied. ResultsOverexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-β1, TGF-β receptor II [Tgf-βrII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1–7 receptor [MasR]) expression, and normalised urinary Ang 1–7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. In vitro, hnRNP F overexpression stimulated Ace-2 gene promoter activity, mRNA and protein expression, and attenuated Agt, Tgf-β1 and Tgf-βrII gene expression. Furthermore, hnRNP F overexpression prevented TGF-β1 signalling and TGF-β1 inhibition of Ace-2 gene expression.Conclusions/interpretationThese data demonstrate that hnRNP F stimulates Ace-2 gene transcription, prevents TGF-β1 inhibition of Ace-2 gene transcription and induction of kidney injury in diabetes. HnRNP F may be a potential target for treating hypertension and renal fibrosis in diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3700-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
MethodsDiabetic nephropathy (DN), a leading cause of endstage renal disease (ESRD), accounts for ∼50% of all ESRD cases [1, 2]
Conclusions/interpretation These data demonstrate that heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates Ace-2 gene transcription, prevents TGF-β1 inhibition of Ace-2 gene transcription and induction of kidney injury in diabetes
We reported that insulin inhibits high glucose stimulation of rat renal Agt gene expression via two nuclear proteins—heterogeneous nuclear ribonucleoproteins F and K—that interact with the Chemicals and constructs Active human recombinant TGF-β1 was obtained from R&D Systems (Minneapolis, MN, USA)
Summary
Diabetic nephropathy (DN), a leading cause of endstage renal disease (ESRD), accounts for ∼50% of all ESRD cases [1, 2]. RPTC-selective overexpression of catalase or pharmacological blockade of the renin–angiotensin system (RAS) attenuates hypertension, ROS generation, kidney injury and normalised RPTC ACE-2 expression in mouse models of diabetes [21,22,23,24]. Taken together, these observations indicate that oxidative stress-induced upregulation of AGT expression and downregulation of ACE-2 expression in RPTCs, resulting in higher angiotensin (Ang)II/Ang 1–7 ratio, may be key determinants of development of hypertension and nephropathy in diabetes. Statistical analysis was performed by the Student’s t test or one-way analysis of variance and the Bonferroni test as appropriate provided by Graphpad Software, Prism 5.0
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