Cellular mediators of renal vascular dysfunction in hypertension

Abstract

The renal vasculature plays a major role in the regulation of renal blood flow and the ability of the kidney to control the plasma volume and blood pressure. Renal vascular dysfunction is associated with renal vasoconstriction, decreased renal blood flow, and consequent increase in plasma volume and has been demonstrated in several forms of hypertension (HTN), including genetic and salt-sensitive HTN. Several predisposing factors and cellular mediators have been implicated, but the relationship between their actions on the renal vasculature and the consequent effects on renal tubular function in the setting of HTN is not clearly defined. Gene mutations/defects in an ion channel, a membrane ion transporter, and/or a regulatory enzyme in the nephron and renal vasculature may be a primary cause of renal vascular dysfunction. Environmental risk factors, such as high dietary salt intake, vascular inflammation, and oxidative stress further promote renal vascular dysfunction. Renal endothelial cell dysfunction is manifested as a decrease in the release of vasodilatory mediators, such as nitric oxide, prostacyclin, and hyperpolarizing factors, and/or an increase in vasoconstrictive mediators, such as endothelin, angiotensin II, and thromboxane A(2). Also, an increase in the amount/activity of intracellular Ca(2+) concentration, protein kinase C, Rho kinase, and mitogen-activated protein kinase in vascular smooth muscle promotes renal vasoconstriction. Matrix metalloproteinases and their inhibitors could also modify the composition of the extracellular matrix and lead to renal vascular remodeling. Synergistic interactions between the genetic and environmental risk factors on the cellular mediators of renal vascular dysfunction cause persistent renal vasoconstriction, increased renal vascular resistance, and decreased renal blood flow, and, consequently, lead to a disturbance in the renal control mechanisms of water and electrolyte balance, increased plasma volume, and HTN. Targeting the underlying genetic defects, environmental risk factors, and the aberrant renal vascular mediators involved should provide complementary strategies in the management of HTN.

Fig. 1.

Mediators of renal vasoconstriction and hypertension (HTN). Genetic mutation of an ion channel or transporter, combined with dietary factors, oxidative stress, inflammatory response, and mental stress, cause vascular, renal, and neural dysfunction. Endothelial dysfunction causes a decrease in vasodilators (VDs) [nitric oxide (NO), prostacyclin (PGI₂), endothelium-derived hyperpolarizing factor (EDHF)] and an increase in vasoconstrictors (VCs) [angiotensin II (ANG II), endothelin-1 (ET-1), thromboxane A₂ (TxA₂)]. Vascular smooth muscle (VSM) dysfunction is associated with increased Ca²⁺, PKC, Rho kinase, and MAPK and leads to VSM contraction and growth. Sympathetic nerves contribute to VSM hyperactivity. Changes in the expression/activity of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in extracellular matrix (ECM) promote renal vascular remodeling. Excessive renal vasoconstriction increases renal vascular resistance (RVR) and contributes to total vascular resistance. Also, vasoconstriction of preglomerular arterioles decreases renal blood flow (RBF) and filtered NaCl, leading to activation of tubuloglomerular feedback (TGF) and increased release of renin and ANG II, which acts in a paracrine or systemic fashion to induce further vasoconstriction. ANG II also increases aldosterone (Aldo) secretion and stimulates tubular NaCl and water absorption. ANG II-induced vasoconstriction of postglomerular efferent arterioles in the cortex and vasa recta in the medulla further increases NaCl absorption, plasma volume, and blood pressure (BP). HTN, in turn, promotes vascular and renal inflammation and oxidative stress, leading to a vicious cycle and progression of HTN. Not shown, vascular agents could act in a paracrine fashion and affect tubular reabsorption, sympathetic nerves may affect renin release from juxtaglomerular cells (JGCs), and renal afferent nerves may send feedback signals to sympathetic centers. ENaC, epithelial Na channel; ROS, reactive oxygen species; EET, epoxyeicosatrienoic acid; HETE, hydroxyeicosatetraenoic acid; NE, norepinephrine; GFR, glomerular filtration rate.

Fig. 2.

Genetic factors in renal and vascular dysfunction and HTN. Genetic mutation in the Na⁺/H⁺ exchanger (NHE), Na⁺-Cl⁻ cotransporter (NCC), ENaC, Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2), and Na⁺-K⁺ pump in the nephron could lead to sodium and water retention. Changes in Aldo synthesis and mineralocorticoid receptor (MR), as well as ANG II and ANG II type 1 receptor (AT₁R), contribute to sodium absorption. Mutations in the genes expressing ENaC, NHE, and Na⁺/K⁺/2Cl⁻ and Na⁺/Ca²⁺ exchanger (NCX) in VSM could promote renal vasoconstriction and exacerbate HTN.

Fig. 3.

TGF and autoregulation of RBF and renin release. A decrease in RBF is associated with increased neuronal NO synthase (nNOS) activity, NO-mediated renin release by JGC, and formation of ANG II. ANG II inhibits further renin release. Paracrine signaling by macula densa also controls RVR and renin release. Increased luminal NaCl alters macula densa cell Na⁺ concentration, pH, volume, basolateral membrane potential, and intracellular Ca²⁺ concentration ([Ca²⁺]_i). Luminal ANG II via AT₁R and consequent changes in Na/H/X2 exchanger and Cl/HCO₃⁻/X at the apical membrane and Na/H/X4 at the basolateral membrane affect macula densa Na⁺ transport, cell alkalinization, and volume. NaCl entry via apical NKCC2 and Cl exit through basolateral channel lead to cell depolarization and increased [Ca²⁺]_i. Moderate increases in luminal NaCl prompt macula densa cells to release the VCs TxA₂ and ATP and to decrease vasodilation by prostaglandin E₂ (PGE₂). ATP diffuses through ATP-permeable maxi-anion channels and stimulates P₂ receptors and vasoconstriction. ATP is also dissociated to adenosine, which binds to A₁ and A₄ receptors, causing further afferent arteriolar constriction and decreased renin release from JGCs. Macula densa intracellular Na⁺ is also regulated by apical Na⁺-K⁺-ATPase. Normally, large increases in luminal NaCl stimulate the release of NO, which prevents excessive TGF-mediated vasoconstriction. An increase in oxidative stress and superoxide (O₂^•−) decreases NO bioactivity and antagonizes its inhibitory effect on TGF. ACE, angiotensin-converting enzyme.

Fig. 4.

Endothelium-derived renal VDs and VCs in HTN. In renal vascular endothelial cells, Ca²⁺ release from the endoplasmic reticulum (ER) increases endothelial NO synthase (eNOS) activity and NO production. NO diffuses into renal VSM cells, activates guanylate cyclase (GC), and increases cGMP. cGMP causes VSM relaxation by inhibiting Ca²⁺ influx and stimulating Ca²⁺ extrusion mechanisms. Activation of cyclooxygenases (COX) increases PGI₂ production, which activates adenylate cyclase (AC) and increases cAMP in VSM. cAMP causes VSM relaxation by mechanisms similar to those of cGMP. Renal endothelial release of EDHF, such as certain EETs, activates K⁺ channels and causes hyperpolarization of VSM and inhibition of Ca²⁺ influx through Ca²⁺ channels. The endothelium also releases ET-1, ANG II, and TxA₂, which act on specific receptors in VSM to cause renal vasoconstriction. Activation of endothelial ET_B1R and AT₂R is coupled to increased release of VDs and renal VSM relaxation. A decrease in endothelium-derived VDs and an increase in endothelium-derived VCs are associated with renal vasoconstriction, increased RVR, and HTN. IP₃, inositol trisphosphate; PIP₂, phosphatidylinositol 4,5-bisphosphate; DAG, diacyglycerol; TP, thromboxane-prostanoid; SR, sarcoplasmic reticulum.

Fig. 5.

Regulation of RBF by VCs and VDs. Decreased RBF is associated with increased renin and ANG II release. The vasoconstrictive effects of ANG II and other VCs are normally counterbalanced by VDs, such as NO and PGI₂, leading to maintained RBF and GFR. When the release of VD mediators is compromised, ANG II acts unopposed to induce renal vasoconstriction, leading to decreased RBF and GFR, which, in turn, promote renin release, further activate renin-angiotensin system, and lead to progression of HTN.

Fig. 6.

Differential distribution of receptors and mediators in the renal vasculature and nephron. Renal vascular receptors (shown in red) are activated by VCs to regulate RBF in afferent and efferent arterioles and vasa recta. VDs prevent excessive renal vasoconstriction. Decreased VDs and increased VCs lead to renal vasoconstriction and HTN. Receptors in tubules, loop of Henle, and collecting ducts (shown in brown) are modulated by substances that promote sodium retention or excretion and thereby maintain water and electrolyte balance, plasma volume, and BP. Increased sodium and water retention lead to increased plasma volume and HTN. AVP, arginine-vasopressin.

Fig. 7.

Mechanisms of renal VSM contraction in HTN. Increased VC agonists, such as ET-1, ANG II, or phenylephrine (Phe), activate their receptor (R), stimulate PLC-β, and increase IP₃ and DAG. IP₃ stimulates Ca²⁺ release from the SR. Ca²⁺ stimulates ryanodine-sensitive receptors (RyR) in SR and further releases intracellular Ca²⁺ [Ca²⁺-induced Ca²⁺ release (CICR)]. Agonists also stimulate Ca²⁺ influx through voltage-gated (VGC), ligand-gated (LGC), and store-operated channels (SOC). Ca²⁺ binds calmodulin (CAM), activates myosin light chain (MLC) kinase (MLCK), causes MLC phosphorylation, and initiates renal VSM contraction. Ca²⁺ mobilization mechanisms are normally counterbalanced by Ca²⁺ and Na⁺ extrusion via plasmalemmal Ca²⁺-ATPase, Na⁺-K⁺-ATPase, and NCX and NHE to maintain [Ca²⁺]_i and intracellular pH. DAG activates PKC. PKC induces phosphorylation (P) of CPI-17, which inhibits MLC phosphatase and enhances myofilament Ca²⁺ sensitivity. PKC-induced phosphorylation of calponin (Cap) allows more actin to bind myosin. PKC also activates protein kinase cascades involving Raf, MAPK kinase (MEK), and MAPK, leading to phosphorylation of the actin-binding protein caldesmon (CaD). Also, RhoA/Rho kinase inhibits MLC phosphatase and further enhances the Ca²⁺ sensitivity of the contractile proteins. Significant increases in renal VSM [Ca²⁺]_i and the Ca²⁺-sensitization pathways of VSM contraction cause renal vasoconstriction, increased RVR, and HTN. AA, arachidonic acid; G, GTP-binding protein; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine.