Abstract 054: Tissue-Specific Effects of Targeted Mutation of Mir29b1 in Rats

Abstract

miR-29 is a master regulator of extracellular matrix genes and is generally considered anti-fibrotic, and it improves nitric oxide (NO) production in human and rat arterioles by targeting Lypla1.Targeted mutation in the Mir29b1 gene exacerbates hypertension in a rat model derived from the Dahl salt-sensitive rat. The kidney, particularly the renal outer medulla, plays a key role in the development of salt-sensitive hypertension. In the present study, we examined the effect of the targeted Mir29b1 mutationon tissue fibrosis and NO levels with a focus on kidney regions. The abundance of miR-29b and the co-transcribed miR-29a was substantially lower in the renal cortex, renal outer medulla, heart and liver in mutant rats. In mutant rats on a 0.4% NaCl diet and prior to the development of overt hypertension, tissue fibrosis was significantly increased in the renal outer medulla, but not in the renal cortex, heart or liver, compared with wild-type littermates. Levels of NO metabolites were significantly lower, and Lypla1 protein abundance significantly higher, in the renal outer medulla, but not in the renal cortex. After 14 days of a 4% NaCl diet, tissue fibrosis remained significantly higher in the renal outer medulla and became higher in the heart of mutant rats compared with wild-type littermates, but not in the renal cortex. 24h urine volume was significantly lower in mutant rats on either the 0.4% or 4% NaCl diet. Microalbuminuria was exacerbated by the 4% NaCl diet, but was not significantly different between mutant rats and wild-type littermates. These findings indicate the effects of miR-29 are tissue-specific. 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.