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.

circGlis3 promotes β-cell dysfunction by binding to heterogeneous nuclear ribonucleoprotein F and encoding Glis3-348aa protein

“… 46 In addition, hnRNPF has been reported to be implicated in the kidney injury in diabetic mice by regulating the transcription of a series of genes, including Sirt1 and Ace2 . 30 , 31 , 32 , 33 , 34 Consistently, our study uncovered that in β cells, hnRNPF could activate the transcription of Sirt1 , a NAD + -dependent histone deacetylase that regulates insulin secretion and promotes β-cell survival by deacetylating histones and a dozen nonhistone proteins. 47 , 48 Furthermore, we found that knockdown of hnRNPF induced β-cell dysfunction by reducing Sirt1 expression levels, suggesting that hnRNPF may play an important role in maintaining β-cell function.…”

“… 29 Studies have shown that hnRNPF participated in kidney injury in diabetic mice. 30 , 31 To further elucidate the functional roles of hnRNPF in β cells, hnRNPF was knocked down using siRNAs ( Figure 3 A). Silencing hnRNPF significantly reduced cell viability and proliferation, inhibited insulin secretion, and increased cell apoptosis in MIN6 cells and islets, suggesting an important role of hnRNPF in regulating β-cell function ( Figures 3 B–3F and S3 A–S3C).…”

Selective sodium-glucose cotransporter-2 inhibitors in the improvement of hemoglobin and hematocrit in patients with type 2 diabetes mellitus: a network meta-analysis

“…This may allow myofibroblasts in the mesenchyme to reverse to some extent to erythropoietin-producing fibroblasts, enhancing the hematopoiesis and elevating hematocrit ( 49 ). Some other studies suggest that SGLT2i can prevent damage to renal mesenchymal cells by reducing the activity of the SGLT2 pathway on proximal tubular cells, and this will maintain an adequate erythropoietin level, and subsequently increase hemoglobin and hematocrit levels ( 50 , 51 ). It has also been found in other studies that the increase of hematocrit may be closely related to the correction of sympathetic hyperfunction, leading to the reduction of cardiovascular mortality and the risk of hospitalization due to heart failure ( 52 ).…”

A biomimetic renal fibrosis progression model on-chip evaluates anti-fibrotic effects longitudinally in a dynamic fibrogenic niche

“…3,4 The most effective treatment to improve the survival rate of ESRD patients is kidney transplantation; however, insufficient kidney donors and prohibitively high cost make it impossible for many ESRD patients to receive kidney transplantation. 5 New agents such as SGLT2 inhibitors and finerenone have shown the capability to reduce the progression of chronic kidney disease (CKD) by inhibiting the angiotensin converting enzyme or blocking angiotensin receptors, 6,7 and these two drugs stand a high chance of curbing the progression of renal fibrosisa common pathological finding in CKD. However, no drugs have yet been approved by the FDA specifically for treating renal fibrosis.…”