Albuminuria indicates the pressure-associated injury of juxtamedullary nephrons and cerebral strain vessels in spontaneously hypertensive stroke-prone rats

Abstract

Albuminuria is an indicator of renal injury and is closely linked with cardiovascular disease (CVD). However, the mechanism by which albumin is excreted in the urine remains unclear. As the juxtamedullary region of the kidney is highly susceptible to pressure increase, juxtamedullary injury is observed from an early phase in hypertensive rat models. Anatomical similarities are observed between the pre-glomerular vessels of the juxtamedullary nephron and the cerebral vasculature. We previously named these ‘strain vessels' for their high vascular tone and exposure to higher pressures. The current studies were designed to determine whether albuminuria is the result of juxtamedullary nephron injury, indicating the presence of pressure injury to the strain vessels in spontaneously hypertensive stroke-prone rats (SHR-SP) fed a high-salt diet. Albuminuria was associated with juxtamedullary nephron injury, and the enhanced expression of monocyte chemotactic protein-1 (MCP-1) and tumor growth factor-beta (TGF-β) in 12-week-old SHR-SP rats fed a 4% high-salt diet from the age of 6 weeks. The wall thickness of the pre-glomerular vessels of the juxtamedullary nephron was also associated with that of the perforating artery of the middle cerebral artery. Reducing the blood pressure with nifedipine reduced the degree of albuminuria and juxtamedullary nephron injury as well as MCP-1 and TGF-β expression in the SHR-SP rats fed an 8% high-salt diet from the age of 9 weeks. Nifedipine inhibited stroke events in these animals until they were 14 weeks old. These results indicate that albuminuria is a result of juxtamedullary nephron injury and a marker of pressure-induced injury of the strain vessels.

Association of Kidney Disease Measures With Ischemic Versus Hemorrhagic Strokes

“…24 In fact, an association of albuminuria with increased risk of deep or infratentorial microbleeds, which anatomically correspond with the brain “strain vessels,” has been reported. 25, 26 It could be argued that blood pressure may be in the causal pathway for the association of kidney measures with stroke, and therefore adjustment for blood pressure may have resulted in conservative estimates. Indeed the relative risks of both stroke types for albuminuria became higher when systolic blood pressure and antihypertensive drug use were dropped from the model (Supplemental Figure II).…”

Remodeling of Afferent Arterioles From Mice With Oxidative Stress Does Not Account for Increased Contractility but Does Limit Excessive Wall Stress

“…On the other hand, an increase in afferent arteriolar wall thickness in SOD gene-deleted mice permits an increase in active wall tension with PP during generation of O 2 ·− , as required for enhanced myogenic responses, without an increase in active wall stress. The renal, cerebral, and epicardial resistance arterioles are exposed directly to high levels of pressure and are designated “strain vessels” 21, 22 . The finding that afferent arteriolar wall tension can be dissociated from active wall stress suggests that microvascular remodeling may be an adaptive response to prevent the potentially damaging vascular effects of wall stress while permitting the beneficial effects of enhanced wall tension that are required for strong myogenic responses to maintain autoregulation and prevent the damaging effects of hypertension on the renal parenchyma.…”

“…Myogenic and ANG II responses were related to remodeling and to the generation of arteriolar O 2 ·− but these were dissociated by incubation of arterioles with pegalated (PEG) SOD or PEG-catalase (to metabolize ROS without changing remodeling) or from short-term induction of SOD-3 knockout (to increase ROS without remodeling). Active wall stress (AWS = AWT/wall thickness) normally increases with contractility and has been proposed to contribute to microvascular damage 21, 22 . Therefore, we related contractility to active wall tension and active wall stress to determine their roles in the functional adaption to a prolonged increase in afferent arteriolar ROS.…”

In Vitro Study of the Juxtaglomerular Apparatus and Its Implications in the Chronic Kidney Disease

“…[46][47][48] Such distinct localization of glomerular injuries and mode of progression may be related to anatomic and functional heterogeneities of different nephron populations.…”

“…Indeed, we have shown that in stroke-prone spontaneously hypertensive rats fed a high-salt diet, hypertensive vascular damages occur predominantly in juxtamedullary afferent arterioles, and that the degree of arteriolar damages of the juxtamedullary nephron correlated well with that of perforating arteries of the middle cerebral artery. 46 Coronary arteries can also be regarded as strain vessels. They arise directly from the aorta, and during the systolic phase, the entire epicardial segments of coronary arteries are exposed to a high pressure.…”