Deletion of heterogeneous nuclear ribonucleoprotein F in renal tubules downregulates SGLT2 expression and attenuates hyperfiltration and kidney injury in a mouse model of diabetes

Abstract

Aims/hypothesis: We previously reported that renal tubule-specific deletion of heterogeneous nuclear ribonucleoprotein F (Hnrnpf) results in upregulation of renal angiotensinogen (Agt) and downregulation of sodium-glucose co-transporter 2 (Sglt2) in Hnrnpf^RT knockout (KO) mice. Non-diabetic Hnrnpf^RT KO mice develop hypertension, renal interstitial fibrosis and glycosuria with no renoprotective effect from downregulated Sglt2 expression. Here, we investigated the effect of renal tubular Hnrnpf deletion on hyperfiltration and kidney injury in Akita mice, a model of type 1 diabetes.

Methods: Akita Hnrnpf^RT KO mice were generated through crossbreeding tubule-specific (Pax8)-Cre mice with Akita floxed-Hnrnpf mice on a C57BL/6 background. Male non-diabetic control (Ctrl), Akita, and Akita Hnrnpf^RT KO mice were studied up to the age of 24 weeks (n = 8/group).

Results: Akita mice exhibited elevated systolic blood pressure as compared with Ctrl mice, which was significantly higher in Akita Hnrnpf^RT KO mice than Akita mice. Compared with Akita mice, Akita Hnrnpf^RT KO mice had lower blood glucose levels with increased urinary glucose excretion. Akita mice developed kidney hypertrophy, glomerular hyperfiltration (increased glomerular filtration rate), glomerulomegaly, mesangial expansion, podocyte foot process effacement, thickened glomerular basement membranes, renal interstitial fibrosis and increased albuminuria. These abnormalities were attenuated in Akita Hnrnpf^RT KO mice. Treatment of Akita Hnrnpf^RT KO mice with a selective A1 adenosine receptor inhibitor resulted in an increase in glomerular filtration rate. Renal Agt expression was elevated in Akita mice and further increased in Akita Hnrnpf^RT KO mice. In contrast, Sglt2 expression was increased in Akita and decreased in Akita Hnrnpf^RT KO mice.

Conclusions/interpretation: The renoprotective effect of Sglt2 downregulation overcomes the renal injurious effect of Agt when these opposing factors coexist under diabetic conditions, at least partly via the activation of tubuloglomerular feedback.

Keywords: Akita mice; Angiotensinogen; Heterogeneous nuclear ribonucleoprotein F; Sodium-glucose co-transporter 2; Type 1 diabetes.