Renal oxidative stress, oxygenation, and hypertension

Abstract

Hypertension is closely associated with progressive kidney dysfunction, manifested as glomerulosclerosis, interstitial fibrosis, proteinuria, and eventually declining glomerular filtration. The postulated mechanism for development of glomerulosclerosis is barotrauma caused by increased capillary pressure, but the reason for development of interstitial fibrosis and the subsequently reduced kidney function is less clear. However, it has been hypothesized that tissue hypoxia induces fibrogenesis and progressive renal failure. This is very interesting, since recent reports highlight several different mechanisms resulting in altered oxygen handling and availability in the hypertensive kidney. Such mechanisms include decreased renal blood flow due to increased vascular tone induced by ANG II that limits oxygen delivery and increases oxidative stress, resulting in increased mitochondrial oxygen usage, increased oxygen usage for tubular electrolyte transport, and shunting of oxygen from arterial to venous blood in preglomerular vessels. It has been shown in several studies that interventions to prevent oxidative stress and to restore kidney tissue oxygenation prevent progression of kidney dysfunction. Furthermore, inhibition of ANG II activity, by either blocking ANG II type 1 receptors or angiotensin-converting enzyme, or by preventing oxidative stress by administration of antioxidants also results in improved blood pressure control. Therefore, it seems likely that tissue hypoxia in the hypertensive kidney contributes to progression of kidney damage, and perhaps also persistence the high blood pressure.

Fig. 1.

Factors determining intrarenal oxygen availability.

Fig. 2.

Relationship between tubular sodium transport (T_Na) and oxygen consumption (Q_O2) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats (WKY). [Redrawn from data originally presented by Welch et al. (123).]

Fig. 3.

Schematic view of the vicious cycle relating tubulointerstitial fibrosis to chronic hypoxia, which creates a self-sustaining mechanism that accelerates the pathological process ending in end-stage renal disease. [Redrawn from the hypothesis presented by Nangaku (75, 76).]

Fig. 4.

Schematic presentation of the known mechanisms resulting in renal tissue hypoxia and kidney damage in hypertension. RAS, renin-angiotensin system.