Intratubular and intracellular renin–angiotensin system in the kidney: a unifying perspective in blood pressure control

Abstract

The renin-angiotensin system (RAS) is widely recognized as one of the most important vasoactive hormonal systems in the physiological regulation of blood pressure and the development of hypertension. This recognition is derived from, and supported by, extensive molecular, cellular, genetic, and pharmacological studies on the circulating (tissue-to-tissue), paracrine (cell-to-cell), and intracrine (intracellular, mitochondrial, nuclear) RAS during last several decades. Now, it is widely accepted that circulating and local RAS may act independently or interactively, to regulate sympathetic activity, systemic and renal hemodynamics, body salt and fluid balance, and blood pressure homeostasis. However, there remains continuous debate with respect to the specific sources of intratubular and intracellular RAS in the kidney and other tissues, the relative contributions of the circulating RAS to intratubular and intracellular RAS, and the roles of intratubular compared with intracellular RAS to the normal control of blood pressure or the development of angiotensin II (ANG II)-dependent hypertension. Based on a lecture given at the recent XI International Symposium on Vasoactive Peptides held in Horizonte, Brazil, this article reviews recent studies using mouse models with global, kidney- or proximal tubule-specific overexpression (knockin) or deletion (knockout) of components of the RAS or its receptors. Although much knowledge has been gained from cell- and tissue-specific transgenic or knockout models, a unifying and integrative approach is now required to better understand how the circulating and local intratubular/intracellular RAS act independently, or with other vasoactive systems, to regulate blood pressure, cardiovascular and kidney function.

Dietary Potassium Downregulates Angiotensin-I Converting Enzyme, Renin, and Angiotensin Converting Enzyme 2

“…Angiotensin-I converting enzyme plays a key role in intrarenal vasoactive peptide systems. The enzyme transforms angiotensin I into angiotensin II inducing vasoconstriction and also inactivates bradykinin, a vasodilator peptide (Li et al, 2018). In our experiments, ACE immunolocalization was mainly present in the brush border of epithelial cells of proximal straight tubules although ACE had been localized also in mesangial cells and collecting duct (Redublo Quinto et al, 2007).…”

“…The intrarenal renin-angiotensin system may also contribute to hypertension. Renin enzyme can reach the proximal tubule that express angiotensinogen, angiotensin-I converting enzyme (ACE), and AT1 receptors in the apical domain of proximal tubule and distal convoluted tubule producing angiotensin II that contributes to hypertension through the stimulation of NaCl reabsorption in the proximal and distal convoluted tubule (Velez, 2009;Gurley et al, 2011;Li et al, 2018).…”

“…Therefore, either an acute or chronic potassium loading results in a reduction of plasma renin activity. Since renin can be filtered in the glomerular barrier (Li et al, 2018), a decrease in filtered renin implies a decrease in formation of angiotensin I from angiotensinogen, which can be secreted by FIGURE 5 | Renin mRNA abundance in control (NK) and high potassium (HK) diet. Renin mRNA abundance is reduced in rats with chronic high potassium diet compared to control rats (mean ± SEM; n = 11; **P < 0.01).…”

The Intratubular and Intracrine Renin-Angiotensin System in the Proximal Tubules of the Kidney and Its Roles in Angiotensin II-Induced Hypertension

“…Previous studies have shown that single cell microinjection or microdialysis of ANG II directly into the cells may distinguish between the effects induced by extracellular ANG II from those induced by intracellular ANG II [15, 102,[174][175][176][177]. Indeed, we have demonstrated that intracellular microinjection of ANG II directly into single rabbit proximal tubule cells induced intracellular [Ca 2+ ] i responses ( Figure 3) [10,15,16,81,177]. We further reported that microinjection of the AT 1 blocker losartan abolished the [Ca 2+ ] i response induced by microinjected ANG II, but it only partially blocked the effects of extracellular ANG II [15].…”

“…There is accumulating evidence that ANG II acts not only as an endocrine or paracrine hormone activating cell surface ANG II receptors, but also as an intracellular or intracrine peptide activating intracellular ANG II receptors, though the precise roles of the latter remain largely unknown [9][10][11]. Indeed, in addition to activating cell surface ANG II receptors, circulating and paracrine ANG II can readily enter the cells via AT 1 receptor-mediated endocytosis.…”