Abstract
Clinical data suggests an association between systolic hypertension, renal function and hyperhomocysteinemia (HHcy). HHcy is a state of elevated plasma homocysteine (Hcy) levels and is known to cause vascular complications. In this study, we tested the hypothesis whether Ang II-induced hypertension increases plasma Hcy levels and contributes to renovascular remodeling. We also tested whether folic acid (FA) treatment reduces plasma Hcy levels by enhancing Hcy remethylation and thus mitigating renal remodeling. Hypertension was induced in WT mice by infusing Ang II using Alzet mini osmotic pumps. Blood pressure, Hcy level, renal vascular density, oxidative stress, inflammation and fibrosis markers, and angiogenic- and anti-angiogenic factors were measured. Ang II hypertension increased plasma Hcy levels and reduced renal cortical blood flow and microvascular density. Elevated Hcy in Ang II hypertension was associated with decreased 4, 5-Diaminofluorescein (DAF-2DA) staining suggesting impaired endothelial function. Increased expression of Nox-2, -4 and dihydroethidium stain revealed oxidative stress. Excess collagen IV deposition in the peri-glomerular area and increased MMP-2, and -9 expression and activity indicated renal remodeling. The mRNA and protein expression of asymmetric dimethylarginine (ADMA) was increased and eNOS protein was decreased suggesting the involvement of this pathway in Hcy mediated hypertension. Decreased expressions of VEGF and increased anti-angiogenic factors, angiostatin and endostatin indicated impaired vasculogenesis. FA treatment partially reduced hypertension by mitigating HHcy in Ang II-treated animals and alleviated pro-inflammatory, pro-fibrotic and anti-angiogenic factors. These results suggest that renovascular remodeling in Ang II-induced hypertension is, in part, due to HHcy.
Highlights
Renovascular injury and fibrosis due to angiotensin II (Ang II) is a leading cause of cardio-renovascular morbidity and mortality
Our study suggests that Ang II hypertension causes elevation in plasma homocysteine (Hcy) levels aggravating blood pressure and renovascular remodeling
HHcy in Ang II hypertension occurs as a result of impaired remethylation and transulfuration processes due to decrease in methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta synthase (CBS)/cystathionine gamma lyase (CSE) enzymes respectively
Summary
Renovascular injury and fibrosis due to angiotensin II (Ang II) is a leading cause of cardio-renovascular morbidity and mortality. Clinical data suggest an association between elevated levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), and systolic hypertension [1]. Ang II has predominant actions on the renal vasculature causing a reduction in renal blood flow, the effect of HHcy and its contribution to renovascular remodeling in Ang II-induced hypertension is unclear. TIMP-1, -2 and -4 mediate their action by blocking the MMPs’ catalytic core, whereas TIMP-3 binds to ECM and protects it from MMP mediated injury [14]. TIMPs regulate ECM by inhibiting MMPs. HHcy induces MMP-2, -9 [13] and modulates TIMPs [15] to promote matrix accumulation [16]; whether a similar mechanism is involved in Ang II-induced kidney remodeling has not been reported
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