There is general acknowledgment that the kidney plays a pivotal role in the regulation of body fluid volume and blood pressure, and that angiotensin II (Ang II) and vasopressin (AVP) participate in these regulations through multiple direct and indirect effects exerted on renal blood flow and water electrolyte transport. Excessive activation of RAS and AVP under pathological conditions is involved in the generation of a common set of features typical for a progressive renal damage.

All components of the renin-angiotensin system, namely prorenin, renin, angiotensinogen, angiotensin converting enzymes (ACE and ACE2) and other enzymes necessary for formation of a specific angiotensin as well as angiotensin receptors (AT1R, AT2R and Mas) are present in the kidney. The receptors can be stimulated by angiotensin peptides supplied into the kidney from the systemic circulation or by those generated locally in the kidney. Specialized juxtaglomerular (JG) granular cells, which derive from smooth muscle cells, and which are situated in the wall of the afferent arteriole of the kidney, are the most abundant source of prorenin and renin in the body. The JG cells are located in close vicinity to specialized granular epithelial cells of the macula densa of the distal tubule. Both groups of juxtaglomerular and macula densa cells are situated in the angle between the afferent and efferent arteriole. Renin is also synthesized in the principal cells of the collecting ducts (CD) (1-5).

The renal RAS can be activated by multiple hemodynamic, endocrine and chemical factors. Even small decreases of intraglomerular hydrostatic pressure, caused by relaxation of afferent sympathetic arteriole, as well as small decreases of NaCl delivery to the macula densa are able to elicit significant increase of renin release. In addition, sympathetic innervation of the kidney exerts tonic excitatory effect on secretion of renin by JG cells. Nitric oxide (NO) and prostaglandin E2 which are released by the macula densa cells as a result of reduced sodium delivery to the proximal tubule, and which act in the mechanism of the tubuloglomerular feedback, cause increase of cGMP and cAMP in JG cells and subsequent release of renin. Systemic hypovolemia or hypotension are also potent stimuli of intrarenal renin release. They can act directly by decreasing intraglomerular pressure, or indirectly by unloading systemic baroreceptors and subsequent activation of the sympathetic nervous system (1, 4-7). Hypoxia, which can act either directly on the renin-secreting cells or indirectly by stimulating peripheral chemoreceptors, and subsequently activating the sympathetic nervous system, is another powerful stimulus for renin release (8, 9). There is also evidence for stimulation of renin release by vasopressin. Although earlier studies suggested that systemic AVP administration inhibits release of renin, the later investigations demonstrated that this was an indirect effect, related to AVP-induced increase of blood pressure (10). It has been also shown that local stimulations of V2 receptors (V2R) by AVP and of AT1 receptors (AT1R) by Ang II elevate synthesis of renin in CD cells (11, 12).

Vasopressin secreting neurons are located mainly in the supraoptic and paraventricular nuclei of the hypothalamus and are releasing AVP to the systemic circulation and into specific regions of the brain in response to hyperosmolality, Ang II, unloading of baroreceptors, and stimulation of chemoreceptors and/or afferent renal nerves (13-15). Angiotensin receptors located on vasopressinergic neurons can be stimulated either by angiotensin peptides produced locally in the brain or by those reaching the brain from the systemic circulation via the circumventricular organs (16, 17).

In the kidney, AT1R and AT2R proteins or genes were identified in walls of vessels and tubules. In particular, they were found in the arcuate arteries, afferent arterioles and outer medullary descending vasa recta, and in the proximal tubule, thick ascending limb (TALH) of the loop of Henle, and the collecting duct (3, 18, 19). Prolonged exposure of cultured proximal tubule cells to Ang II results in concentration-dependent increases of AT1R density (20). The Mas receptors for Ang-(1-7) are located mainly in proximal tubules and presumably their stimulation acts oppositely to activation of Ang II (21). The studies in which cultured renal cells were exposed to Ang II, ACE inhibitors or AT1R antagonists, and experiments with intrarenal infusions of these compounds provided evidence that Ang II increases contractility of smooth muscle cells and induces vasoconstriction. It has been shown that Ang II constricts afferent and efferent arterioles, reduces the cortical and papillary blood flow, enhances sodium absorption in the proximal tubule and inhibits tubuloglomerular feedback. Prolonged exposure to Ang II may cause renal injury (5, 22, 23).

Similarly as Ang II, vasopressin exerts a variety of biological effects by means of specific G-protein-coupled receptors, designated V1a, V1b and V2. Vasopressin V1aR are necessary for vasoconstriction, cellular proliferation, platelet aggregation and metabolic effects of AVP, whereas V2R participate in the regulation of body fluid homeostasis (24, 25). Receptors of V1aR subtype were found in the interlobular arteries, efferent arterioles, vasa recta, glomerular mesangium, juxtaglomerular apparatus, macula densa, tubular ascending loop of the loop of Henle, and the collecting duct principal and alpha intercalated cells (25, 26). Activation of V1aR initiates cellular responses regulated by phospholipase C/diacylglycerol - IP3-STAT-protein kinase C pathway (27-29).

There is evidence for an interaction between Ang II and AVP in the regulation of smooth muscle tone. Experiments on preglomerular arterioles have shown that both Ang II and AVP produce significant increases in Ca²⁺ intracellular concentration, which depend on stimulation of AT1 and V1 receptors and engages activation of dihydropyridine-sensitive voltage-gated calcium channels (30). Strong evidence argues for positive interaction of AVP and Ang II with regard to calcium mobilization, which means that a combination of subthreshold doses of these peptides elicits significant cytosolic Ca²⁺ mobilization in vascular smooth muscle cells, though separate administration of the same doses is not effective. In addition, application of both peptides simultaneously increases intracellular Ca²⁺ in a more than additive manner (31).