Losartan chemistry and its effects via AT1 mechanisms in the kidney

Abstract

Besides the importance of the renin-angiotensin system (RAS) in the circulation and other organs, the local RAS in the kidney has attracted a great attention in research in last decades. The renal RAS plays an important role in the body fluid homeostasis and long-term cardiovascular regulation. All major components and key enzymes for the establishment of a local RAS as well as two important angiotensin II (Ang II) receptor subtypes, AT1 and AT2 receptors, have been confirmed in the kidney. In additional to renal contribution to the systemic RAS, the intrarenal RAS plays a critical role in the regulation of renal function as well as in the development of kidney disease. Notably, kidney AT1 receptors locating at different cells and compartments inside the kidney are important for normal renal physiological functions and abnormal pathophysiological processes. This mini-review focuses on: 1) the local renal RAS and its receptors, particularly the AT1 receptor and its mechanisms in physiological and pathophysiological processes; and 2) the chemistry of the selective AT1 receptor blocker, losartan, and the potential mechanisms for its actions in the renal RAS-mediated disease.

Fig. (1). Chemistry comparison between losartan and Ang II

The leading compound (S-8307/S-8308) is modified in its benzyl side chain for more hydrophobicity and oral bioavailability. Addition of the tetrazole group is mimic the anion charges in the N-terminal of Ang II. The lower part of figure indicates several parts in losartan, which are closly mimic those in Ang II: the imidazole ring and the n-butyl side chain in losartan is mimicing the side chains of His⁶ and Ile⁵ in the COOH-terminal of Ang II; the anion charged tetrazole ring in the para-position of losartan is well fitting that in Asp¹ and Tyr⁴ of the Ang II NH₂-terminal residues.

Fig. (2). Losartan and RAS-mediated activation

This figure shows that increased intrarenal Ang II (either unltrafiltered from the glomerulus or the renal local tissue) activates AT1 receptors, in the proximal tubular cell followed by expression of angiotensinogen, renin, and ACE. As a result, angiotensinogen and Ang I are catalyzed in situ, and to be released to the extracellular space (as well as the tubular space). Losartan can directly abrogate AT1 receptors. Moreover, the proximal tubule is innervated by renal sympathetic nerve termini, whose subsequent catecholamine in turn stimulates α₂/β₁ receptors. AT1 receptors are located at the nerve terminals. Losartan is able to attenuate activation of intrarenal RAS by inhibiting renal sympathetic outflow.

Fig. (3). Losartan and renal tubule functions

A. In the proximal tubules (PT), increased intraluminal Ang II can, via AT1 receptors, directly stimulate type 3 Na⁺-H⁺ cotransporter (NHE3) and H⁺ pump (V-type H⁺-ATPase) in the apical membrane, and Na⁺-K⁺ ATPase and type 1-A of the eletrogenic Na⁺-3HCO₃⁻ cotransporter (NBCe1-A) in the basolateral membrane, as well as the protein trafficking of NHE3 and vacuolar H⁺ pump toward the apical membrane. As a result, Na⁺ reabsorption and H⁺ secretion will be increased. Elevated H⁺ in the lumen would then to form carbonic acid together with the luminal HCO₃⁻. Then, membrane-bond type IV of the carbonic anhydrase (CAIV) is able to catalyze H₂CO₃ into water and carbon dioxide. Subsequently, almost all H₂O and majority of CO₂ would pass through the gas/water channel aquaporin 1 (AQP1) into the cytoplasm, while very limited CO₂ diffuses into the cytoplasm. Soluble type II carbonic anhydrase (CAII) can condense H₂O and CO₂ to re-create H₂CO₃ in the cytoplasm. Finally, the HCO₃⁻ and H⁺ from H₂CO₃, are transported to the interstitium and lumen by H⁺ pump and NBCe1-A, respectively. Thus, in the proximal tubules, losartan can lower sodium and bicarbonate together with water absorption and lessen tubular acidification via AT1 receptors locating in either the apical and basolateral surface. B. In the thick ascending limb of loop of Henle (TAL), Ang II can inhibit Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) or bumetanide-sensitive channel-1 (BSC-1), and type 2 NHE (NHE2) in the apical membrane of the TAL. However, abnormal or persisted increased intrarenal Ang II can increase expression of BSC-1 and NHE2 and stimulate apical ROMK potassium channel on both apical and basolateral surface. The apical BSC-1 and ROMK can be interdependent to facilitate NaCl transepithelial transport. The Na⁺-K⁺ ATPase, type 4 K⁺-Cl⁻ cotransporter (KCC4), and kidney specific chloride channel (CLC-K, K1 or K2 subtype), especially K2 subtype, whereas in distal convoluted tubules (DCT), in the basolateral membrane are coupled for transepithelial transport of Na⁺ and Cl⁻. The mechanism of bicarbonate reabsortion is similar to that in the PT. An increased NaCl and bicarbonate absorption can be effectively attenuated by losartan. As a result, losartan can further lower NaCl gradient in the medulla. C. In the DCT, elevated intrarenal Ang II can stimulate NHE2, amiloride-sensitive Na⁺-Cl⁻ cotransporter (NCC), and H⁺ pump, as well as increase of expression and trafficking of either NCC or H⁺ pump, which are undergoing the AT1 receptor pathway. The subsequent increased bicarbonate and NaCl transepithelial transport are similar to those indicated in A and B. Consequently, in the DCT, losartan may be in part abolish NaCl and HCO₃⁻ transepithelial transport together with inhibiting the tubular over-acidification by abnormal intrarenal Ang II in diseases. D. In the cortical collecting ducts (CCD), activation of AT1 receptor can directly stimulate aldosterone-sensitive epithelial sodium channel (ENaC) and enhance expression of α-subunit of ENaC independent of aldosterone. In addition, AT1 receptor activation can stimulate basolateral 18pS potassium channel, which is related to sodium transepithelial transport. Recent studies indicated that activated AT1 receptors can enhance transepithelial transport of Cl⁻ indirectly via its activation on apical H⁺ pump, which would in turn stimulate Cl⁻ transport by AE2 (Cl⁻-HCO₃⁻ exchanger). Losartan can influence its natriuresis and diuresis in the CCD. E. In the medullary collecting ducts (MCD) [divided into outer and inner medullary collecting ducts (OMCD, IMCD)], Ang II can directly increase expression of apical ENaC and H⁺ pump. Thus, both sodium and bicarbonate transport can be elevated by increased intrarenal Ang II in diseases via the AT1 receptor pathway. Another intriguing phenomenon elicited by AT1 stimulation is that, activity of the apical UT-A1 (urea transporter-A subtype 1), and the trafficking of apical AQP2, can be both activated by Ang II. Consequently, losartan not only can further augment its inhibition of sodium and bicarbonate absorption, and tubular acidification, but also lessen urea gradient in the medulla in order to exquisitely regulate urinary volume and osmolality.