Vascular Mechanisms of Hypertensive Nephropathy

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Hypertensive nephropathy is a common cause of chronic kidney disease (CKD) and is the second leading cause of end-stage kidney disease (ESKD). The prevalence of CKD is significantly higher than the general population and demonstrate progressive loss of kidney function over time, more attention to the underlying mechanisms of hypertensive nephropathy are required. Remodeling of the afferent arterioles and accompanying glomerulosclerosis are hallmarks of human hypertensive nephropathy. Despite extensive investigation, there remain gaps in understanding why some hypertensive patients develop ESKD, while others do not. The molecular pathogenesis of the arteriolar remodeling in hypertensive nephropathy would provide clues to this susceptibility, but the multiple variables that associate with the human condition limit the ability to provide definitive conclusions. Insight into the molecular basis of renal microvascular remodeling may therefore be gained through the study of relevant animal models, in particular the Dahl salt-sensitive (SS) rat, a well-characterized model of hypertensive nephropathy. Our previous studies, which are described in detail in this application, uncovered an intrinsic defect in the structural/functional relationship of the renal microvasculature of SS rats occurring with increases in blood pressure. Preliminary and published studies revealed that hypertension rapidly upregulated expression of both matrix metalloproteinase-9 (MMP-9) and Chemokine (C-C motif) Ligand 2 (CCL2), a potent pro-inflammatory chemokine, in kidney microvasculature of SS rats. We further confirmed that ED-1-positive macrophages collected around the microvessels of hypertensive SS rats. Our combined findings support the working hypothesis that hypertension-induced kidney disease in SS rats is initiated by glomerular injury mediated by microvascular smooth muscle production of a milieu that promotes inflammation, remodeling, and autoregulatory impairment (Fig. 1). We propose 2 aims: Aim 1: Determine the novel mechanisms of renal microvascular remodeling and autoregulatory dysfunction in SS rats. Hypothesis: MMP-9 mediates afferent arteriolar remodeling and impairment of the myogenic response during the development of hypertension. 1.1 Assess renal afferent arteriolar remodeling and autoregulatory behavior and smooth muscle pathobiology of SSMmp9-/- rats. 1.2 Describe the role of kidney-specific versus systemic expression of MMP-9 in microvascular remodeling using a kidney transplant model. Aim 2: Define the mechanisms of the renal microvascular inflammatory process on hypertensive nephropathy in SS rats. Hypothesis: CCL2 is integrally involved in renal microvascular remodeling and autoregulatory impairment in hypertensive SS rats. 2.1 Describe the role of CCL2 in microvascular inflammation and autoregulation in SSCcl2-/- rats. 2.2 Determine the microvascular mechanism of kidney-specific versus systemic expression of CCL2 in hypertensive nephropathy using a model of kidney transplantation. By focusing on the molecular pathogenesis of renal microvascular inflammation and remodeling, impaired autoregulatory response to hypertension and glomerular injury, these studies will improve understanding of the molecular basis of CKD and ESKD from hypertension.