Tissue-specific effects of targeted mutation of Mir29b1 in rats

Abstract

Background miR-29 is a master regulator of extracellular matrix genes, but conflicting data on its anti-fibrotic effect have been reported. miR-29 improves nitric oxide (NO) production in arterioles by targeting Lypla1. Mir29b1 targeted mutation exacerbates hypertension in a model derived from the Dahl salt-sensitive rat. We examined the effect of Mir29b1 mutation on tissue fibrosis and NO levels with a focus on kidney regions. Methods Mir29b1 targeted mutant rats on the genetic background of SS-Chr13 BN rats were studied. Masson trichrome staining, molecular and biochemical assays, metabolic cage studies, and bioinformatic analysis of human genomic data were performed. Findings The abundance of miR-29b and the co-transcribed miR-29a was substantially lower in mutant rats. Tissue fibrosis was significantly increased in the renal outer medulla, but not in the renal cortex, heart or liver in mutant rats on a 0.4% NaCl diet. Lypla1 protein abundance was significantly higher and NO levels lower in the renal outer medulla, but not in the renal cortex. After 14 days of a 4% NaCl diet, 24 h urine volume and urinary sodium excretion was significantly lower in mutant rats, and tissue fibrosis became higher in the heart. NO levels were lower in the renal outer medulla and heart, but not in the renal cortex. Human miR-29 genes are located in proximity with blood pressure-associated single nucleotide polymorphisms. Interpretation The renal outer medulla might be particularly susceptible to the injurious effects of a miR-29 insufficiency, which might contribute to the development of hypertension in Mir29b1 mutant rats.

Inhibition of miRNA‑29a regulates intestinal barrier function in diarrhea‑predominant irritable bowel syndrome by upregulating ZO‑1 and CLDN1

“…miRNA-29 is highly expressed in glioma tumorigenesis (30), pancreatic ductal adenocarcinoma (31) and chronic liver damage (32). It is noteworthy that miRNA-29 has been reported to be involved in the regulation of intestinal permeability and epithelial barrier function (33,34). Consistent with early research (35), the present results demonstrated that miRNA-29a was significantly increased in patients with IBS-D compared with the control, indicating that miRNA-29a serves a role in IBS-D.…”

“…Secondly, since at least two investigators evaluated and agreed to the clinical symptoms, the study was single blinded. Thirdly, a previous study showed that CLDN-1 is the direct target of miRNA-29a (34). We were unable to conclusively determine whether ZO-1 is a direct target of miRNA-29a.…”

Enterococcus faecalis contributes to hypertension and renal injury in Sprague-Dawley rats by disturbing lipid metabolism

“…PLA2G4 is one of the mammalian PLA2 enzymes hydrolyzing phospholipids to release arachidonic acid, which is a precursor for prostaglandins. As a key factor, PLA2G4 contributes to the development of hypertension and renal injury in various animal models [29,30,47,48]. In the present work, we found that the E. faecalis induced expression of Lypla1 and Pla2g4 was later than other lipid metabolic genes, such as Aspg, Plb1 and Gde1, and only in the renal medulla (Fig.…”

Renal lysophospholipase A1 contributes to Enterococcus faecalis-induced hypertension by enhancing sodium reabsorption

“…Especially, the expression of LYPLA1 but not LYPLA2 was markedly elevated in the renal medulla of E. faecalis -induced hypertensive rats. Similar expression pattern of LYPLA1 was also reported in the renal medulla of high-salt fed Dahl salt-sensitive rats ( Xue et al., 2018 ), suggesting it may be involved in sodium homeostasis. Hence, we hypothesized that renal LYPLA1 may contribute to the pathogenesis of E. faecalis -induced hypertension by regulating sodium homeostasis.…”

“…As a lipid-metabolizing enzyme, the increased expression of LYPLA1 in the renal medulla has been reported in high salt-fed Dahl salt-sensitive rats( Xue et al., 2018 ) and E. faecalis -induced hypertensive rats( Zhu et al., 2021 ), but the role of LYPLA1 in the kidney is poorly defined. In this work, we found that the lypla1 knockdown in the kidney dramatically blocked E. faecalis -induced hypertension and sodium reabsorption ( Figure 2 ).…”