Renal Medullary MicroRNAs in Dahl Salt-Sensitive Rats

Abstract

Abstract-MicroRNAs are endogenous repressors of gene expression. We examined microRNAs in the renal medulla of Dahl salt-sensitive rats and consomic SS-13 BN rats. Salt-induced hypertension and renal injury in Dahl salt-sensitive rats, particularly medullary interstitial fibrosis, have been shown previously to be substantially attenuated in SS-13 BN rats. Of 377 microRNAs examined, 5 were found to be differentially expressed between Dahl salt-sensitive rats and consomic SS-13 BN rats receiving a high-salt diet. Real-time PCR analysis demonstrated that high-salt diets induced substantial upregulation of miR-29b in the renal medulla of SS-13 BN rats but not in SS rats. miR-29b was predicted to regulate 20 collagen genes, matrix metalloproteinase 2 (Mmp2), integrin ␤1 (Itgb1), and other genes related to the extracellular matrix. Expression of 9 collagen genes and Mmp2 was upregulated by a high-salt diet in the renal medulla of SS rats, but not in SS-13 BN rats, an expression pattern opposite to miR-29b. Knockdown of miR-29b in the kidneys of SS-13 BN rats resulted in upregulation of several collagen genes. miR-29b reduced expression levels of several collagen genes and Itgb1 in cultured rat renal medullary epithelial cells. Moreover, miR-29b suppressed the activity of luciferase when the reporter gene was linked to a 3Ј-untranslated segment of collagen genes Col1a1, Col3a1, Col4a1, Col5a1, Col5a2, Col5a3, Col7a1, Col8a1, Mmp2, or Itgb1 but not Col12a1. The result demonstrated broad effects of miR-29b on a large number of collagens and genes related to the extracellular matrix and suggested involvement of miR-29b in the protection from renal medullary injury in SS-13 BN rats. (Hypertension. 2010;55:974-982.)

microRNAs in Diabetic Kidney Disease

“…In cell lines from heart, lung, and kidney with TGF-treatment, overexpression of miR-29 suppresses but inhibition of miR-29 promotes expression of fibrotic markers [70,74,75,[78][79][80][81]. Gene delivery of miR-29b either before or after established obstructive nephropathy successfully blocks progressive renal fibrosis in a mouse model of unilateral ureteral obstruction nephropathy [74], providing a strong support of anti-fibrotic properties of miR-29.…”

“…Gene delivery of miR-29b either before or after established obstructive nephropathy successfully blocks progressive renal fibrosis in a mouse model of unilateral ureteral obstruction nephropathy [74], providing a strong support of anti-fibrotic properties of miR-29. Results from heart, lung, and kidneys also demonstrate that the anti-fibrotic effects of miR-29 are mediated through its ability to suppress the ECM-related gene transcription because more than 20 different ECM-related genes have been validated as direct targets of miR-29 by reporter gene assays and some of them are induced by TGF-signaling [75,80,82].…”

Elevated Plasma miR-29a Levels Are Associated with Increased Carotid Intima-Media Thickness in Atherosclerosis Patients

“…Plasma miR-29a was a new biomarker that could play a role in the pathophysiology of atherosclerosis (Hulsmans and Holvoet 2013). Previous studies (Liu et al 2010;Maurer et al 2010;Kriegel et al 2012) have revealed that target genes of miR-29, such as type I and type III collagens, were important in the development of atherosclerosis (Ulrich et al 2016). The usage of miR-29 antagonists may prevent plaque remodelling (Ulrich et al 2016).…”

miRNA Control of Tissue Repair and Regeneration

“…77 Predicted conserved binding sites for the miR29a-c family on the 3 0 -UTR of 20 collagen genes have been identified. 78 This property is unique to the miR-29 family because the predicted binding sites of the collagen genes are not attributed to any sequence homology in their 3 0 -untranslated region. 78 In adults, members of the miR-29 family cause suppression of ECM genes, resulting in tissue repair with a scar.…”

“…78 This property is unique to the miR-29 family because the predicted binding sites of the collagen genes are not attributed to any sequence homology in their 3 0 -untranslated region. 78 In adults, members of the miR-29 family cause suppression of ECM genes, resulting in tissue repair with a scar. Dysregulation of ECM caused by lower miR-29 is associated with fibrosis development in several organs, including the heart, 77 kidney, 79 lung, 80 and liver.…”