bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.12.27.522015

Effects of canagliflozin and irbesartan on renal fibrosis in Dahl salt-sensitive rats

Zhai, J.·Wang, Z.·Zhang, T.·He, L.·Ma, S.·Zhang, G.·Wang, X.·Guo, Y.
View original source ↗Export metadata ↓

Abstract

Hypertension is one of the major contributors to cardiovascular and chronic kidney disease (CKD). Sodium-glucose cotransporter 2 (SGLT2) inhibitors and angiotensin receptor blockers (ARBs) have become the preferred treatment for patients with CKD. However, the renoprotective effects of the combined therapy of the two drugs on hypertensive renal fibrosis are still largely understood. The aim of this study was to compare the antifibrotic effects of canagliflozin, with or without irbesartan, in the kidneys of Dahl salt-sensitive (Dahl SS) rats on a high salt (HS) diet. After the preconditioning stage, Dahl SS rats (n = 47) were divided into 5 experimental groups as follows: low salt control (n=7), HS control (n=10), high salt with canagliflozin (n=10), high salt with irbesartan (n=10), and high salt with canagliflozin plus irbesartan (n=10). Mean food and water intake, body weight (BW), and systolic blood pressure (SBP) were measured during the whole experimental period. After 12 weeks, the rats were euthanized, and the kidneys were excised for histomorphometric evaluation and immunohistochemical evaluation. An HS diet increased SBP, renal fibrosis, expression of fibrotic protein factors, and TGF-{beta}/Smad2/3 pathway compared to the LS group. We found that irbesartan reduced SBP and slowed the loss of renal function. Canagliflozin significantly reduced BW and renal fibrosis and downregulated the TGF-{beta}/Smad2/3 pathway. The combined therapy showed better renoprotection in all outcome parameters. In conclusion, these results indicate that canagliflozin and irbesartan exert different benefits on nephroprotection in salt-sensitive hypertensive rats.

Explore related subjects

molecular biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Zhai, J., Wang, Z., Zhang, T., He, L., Ma, S., Zhang, G., Wang, X., Guo, Y.. 2022-12-27. Effects of canagliflozin and irbesartan on renal fibrosis in Dahl salt-sensitive rats. https://doi.org/10.1101/2022.12.27.522015

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Msp1-dependent extraction promotes ubiquitylation of translocation-stalled mitochondrial precursor proteins

The translocase of the outer membrane (TOM complex) imports more than 1,000 proteins into mitochondria. Clogging of the TOM pore with a precursor protein causes proteotoxic stress and eventually cell death. Two quality control pathways remove translocation-stalled precursor proteins. In the mitochondrial protein translocation-associated degradation (mitoTAD), Ubx2 recruits the cytosolic AAA-ATPase Cdc48 to clear precursor proteins from the TOM complex. In the mitochondrial compromised protein import response (mitoCPR), the stress-induced Cis1 recruits the AAA-ATPase Msp1 to Tom70. The role of Msp1 for the removal of mitochondrial precursor proteins remains unknown. Here, we demonstrate that parallel loss of Msp1 and Ubx2 strongly affects removal of precursor proteins and cell viability. Msp1 and Ubx2 bind independently of import stress and Cis1 to the TOM complex to remove a large variety of precursor proteins. Msp1-dependent extraction promotes ubiquitylation of precursor proteins, which in turn allows Ubx2-recruited Cdc48 to transfer the substrates to proteasomal degradation. We conclude that two AAA-ATPases cooperate in mitochondrial precursor quality control. Msp1-dependent extraction from the TOM complex facilitates precursor ubiquitylation and Cdc48-mediated transfer to proteasomal degradation.

molecular biology↗
bioRxiv2026

Dietary selenium deficiency drives sex-specific circadian disturbance through redox imbalance and causes early systolic dysfunction in mice

Background: Selenium is a vital trace element involved in antioxidant defence and cardiovascular health. Although selenium deficiency is implicated in cardiomyopathies, its early cardiac effects and underlying mechanisms remain poorly defined. Methods: C57BL6/Njr mice were fed either a selenium deficient or control diet for 12 weeks. Systemic selenium status, cardiac function by echocardiography, left ventricular (LV) transcriptomic profiles, redox balance, and circadian pathway markers were assessed, including sex-specific analyses. Results: Selenium deficiency reduced plasma selenium levels without inducing overt cardiac hypertrophy or fibrosis. Echocardiography showed preserved ejection fraction and fractional shortening but reduced global longitudinal strain, indicating early systolic dysfunction. Cardiac stress markers were increased predominantly in male mice. Left ventricular RNA sequencing revealed enrichment of pathways related to cardiac remodelling, redox regulation, mitochondrial function, and circadian rhythm. Additional protein and metabolic analyses supported sex-specific redox circadian alterations, with males showing a more pronounced stress response profile. Conclusions: Dietary selenium deficiency induces early myocardial dysfunction and molecular remodelling before overt cardiac failure. These changes are associated with redox and circadian pathway disruption and show sex specific features, suggesting that selenium contributes to cardiac homeostasis through sex dependent redox circadian regulation.

molecular biology↗
bioRxiv2026

Dysregulation of FMR1 Splicing in Human Fragile X Syndrome

Fragile X Syndrome (FXS) is a neuro-developmental disorder caused by a CGG expansion in FMR1, leading to transcriptional silencing and loss of the encoded protein FMRP. Surprisingly, ~70% of FXS individuals express FMR1, but the RNA is mis-spliced to isoform FMR1-217, composed of exon 1 spliced to a pseudo-exon in intron 1 and cannot produce FMRP. Splice-switching ASOs rescue proper FMR1 splicing and restore FMRP. FMR1-217 mis-splicing increases with CGG repeat length and is negatively correlated with patient IQ. FMR1-217 is associated with ribosome footprints, indicating it is translated into a polypeptide that may impair cognition. R-loops form at the FMR1 locus and extend into the pseudo-exon, but splice-switching ASOs reduce FMR1-217 and elevate FMRP independently of R-loop formation. DRB-based transcription analysis identified impaired Pol II elongation at the 5 prime region of FMR1 in FXS cells, indicated by accumulation of hypophosphorylated Pol II at the transcription start site. Consistent with this, camptothecin-induced Pol II stalling increased FMR1-217 pseudo-exon inclusion. The splicing factors PTBP1 and PTBP2 regulate FMR1-217 splicing in a differentiation stage-dependent manner. Together, these findings indicate that FMR1-217 mis-splicing in FXS is associated with CGG repeat expansion, R-loop formation, impaired co-transcriptional Pol II elongation and context-dependent regulation by PTBP1/PTBP2.

molecular biology↗