A Novel Angiotensin II Type 1 Receptor-associated Protein Induces Cellular Hypertrophy in Rat Vascular Smooth Muscle and Renal Proximal Tubular Cells

Abstract

Angiotensin II stimulates cellular hypertrophy in cultured vascular smooth muscle and renal proximal tubular cells. This effect is believed to be one of earliest morphological changes of heart and renal failure. However, the precise molecular mechanism involved in angiotensin II-induced hypertrophy is poorly understood. In the present study we report the isolation of a novel angiotensin II type 1 receptor-associated protein. Angiotensin II (Ang II) 1 elicits a wide range of physiological responses in a variety of cell types. This octapeptide hormone plays an important role in the regulation of cardiovascular and renal functions via diverse mechanisms (1), which include arteriolar vasoconstriction, stimulation of aldosterone production, and electrolyte homeostasis (2). Although its vasoactive effects were initially considered to be a unique feature for maintaining blood pressure, recent studies have demonstrated that Ang II exerts many other important actions on the cardiovascular and renal systems. For example, Ang II stimulates the growth of diverse cell types, such as vascular smooth muscle cells (VSMC), cardiac myocytes, and proximal tubular cells (3-6), and it increases the expression of enzymes that produce mediators of inflammation (7,8). These observations suggest that Ang II may play an important role in various cardiovascular and renal diseases associated with abnormal cell growth (cellular hypertrophy or cell proliferation) and inflammation, such as hypertension, congestive heart failure, atherosclerosis, postangioplastic restenosis, and renal failure. Clinical trials and animal studies demonstrated that angiotensin-converting enzyme inhibitors and Ang II receptor blockers prevented vascular, left ventricular, and renal proximal tubular cellular hypertrophy (9 -13), supporting the importance of Ang II in the pathogenesis of cardiovascular and renal diseases. In vitro, Ang II has also been shown to stimulate the growth of VSMC and renal proximal tubular cells (hypertrophic effect) as well as cardiac myocytes and fibroblasts (hyperplastic action) (14 -17).

The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease

“…In rat proximal tubular epithelial cells, Ang II induces cellular hypertrophy and activates relevant downstream signal transduction pathways (Wolf et al, 1993;Hannken et al, 1998Hannken et al, , 2000Guo et al, 2004). The Ang II-induced tubular cell hypertrophy is inhibited by ARBs, suggesting that the AT1 receptor contributes to the tubular cell hypertrophy (Chatterjee et al, 1997).…”

Nebivolol Attenuates Maladaptive Proximal Tubule Remodeling in Transgenic Rats

“…This process is disrupted by elevated tissue levels of Ang II. Albumin retrieval can be restored through Ang II blockade [7,9,10,11,12,13,14,15,16,17,18,19,20]. Smaller quantities of filtered proteins that are not retrieved undergo lysosomal degradation before urinary excretion as small peptide fragments [17,21].…”

“…Albumin retrieval can be restored through Ang II blockade [7,9,10,11,12,13,14,15,16,17,18,19,20]. Smaller quantities of filtered proteins that are not retrieved undergo lysosomal degradation before urinary excretion as small peptide fragments [17,21]. This degradation pathway is especially susceptible to metabolic and growth factors such as Ang II, responsible for maladaptive changes in the PTC and consequent tubulointerstitial fibrosis [10,11,12,13,14,15,16,17,18,19,20].…”

Connective Tissue Growth Factor-Mediated Angiotensin II-Induced Hypertrophy of Proximal Tubular Cells

“…Angiotensin II (AngII) has emerged as an important growth factor for vascular, cardiac, and renal cells besides its vasoconstricting effect. AngII stimulates cellular hypertrophy in cultured vascular smooth muscle cells and renal proximal tubular cells, which is believed to be one of the earliest morphological changes of renal remodeling [5]. Blocking the effects of AngII either by AngII-converting enzyme inhibitors (ACEI) or AngII receptor antagonists (ARAs) has been demonstrated successfully preventing the renal fibrogenesis via blocking hemodynamic and non-hemodynamic roles [6, 7].…”