Hypertension exaggerates renovascular resistance via miR-122-associated stress response in aging

Hypertension at advanced age damages microvasculature and initiates many disease conditions including chronic kidney disease (CKD). In the present study, we sought to determine molecular alterations occurring in angiotensin-II (Ang-II)-induced aged kidney.

Old (75-80 weeks) and young (12-14 weeks) wild-type mice (C57BL/6J) were infused with Ang-II (1000 ng/kg per min) for 4 weeks using osmotic minipumps to induce hypertension. Blood pressure, renovascular density, and renal vascular resistance were measured by telemetry, barium angiography, and renal ultrasound, respectively. Molecular analysis was performed by RT-PCR, western blotting, and immunostaining.

Aged hypertensive mice showed significant increase in blood pressure, increased resistive index, and reduced vasculature compared with young mice with Ang-II. The cytoprotective and anti-inflammatory molecule hemeoxygenase-1 (Ho-1) was found to be downregulated in the hypertensive aged mice whereas its putative regulator Bach-1 was increased. Antagonistically, an increase in inflammatory chemokine Mcp-1 was observed in the same mice group along with an increase in extracellular matrix protein, collagen. In addition, DNA damage marker γH2AX was found to be high in hypertensive kidney, especially in aged hypertensive animals along with increased miR-122. Transfection with a mimic of miR-122 into mesangial cells showed an increase of Bach-1 expression and concomitant decease in Ho-1.

Our findings suggest that aged animals fail to counteract hypertensive condition resulting in upregulation of miR-122 and subsequently Bach-1, leading to decreased levels of Ho-1 and an increase in DNA damage and tissue inflammation. Together, these lead to increased collagen deposition thereby causing reduced vascular density and increased renal resistive index.