Endothelin A Receptor Blockade and Endothelin B Receptor Blockade Improve Hypokalemic Nephropathy by Different Mechanisms

Abstract

Abstract. Hypokalemia causes renal tubulointerstitial injury with an elevation in renal endothelin-1 (ET-1). It was hypothesized that hypokalemic tubulointerstitial injury is ameliorated by the blockade of ET-A receptors (ETA), whereas ET-B receptor (ETB) antagonism may exacerbate the injury, because ETB is thought to mediate vasodilation. Rats were fed a K ϩ -deficient diet alone (LC) or with an ETA-selective antagonist ABT-627 (LA) or an ETB-selective antagonist A-192621 (LB) for 8 wk. Control rats were on a normal K ϩ diet alone or with the ETA-selective or ETB-selective antagonists. The severity of hypokalemia was not significantly different among LA, LB, and LC. LC developed tubulointerstitial injury with an elevation of renal preproET-1 mRNA level. There was an increase in tubular osteopontin expression, macrophage infiltration, collagen accumulation, and tubular cell hyperplasia.ETA blockade significantly ameliorated all parameters for renal injury in the cortex without suppressing local ET-1 and ETA expression. By contrast, ETB blockade significantly reduced local ET-1 and ETA expression and improved the injury to a similar extent in the cortex. In the medulla, ETA or ETB blockade only partially blocked renal injury. ETA blockade did not affect BP in normokalemic or hypokalemic rats. ETB blockade induced a BP elevation with a decrease in urinary Na ϩ excretion in normokalemic but not in hypokalemic rats. These results indicate that ET-1 can mediate hypokalemic renal injury in two different ways: by directly stimulating ETA and by locally promoting endogenous ET-1 production via ETB. Thus, ETA as well as ETB blockade may be renoprotective in hypokalemic nephropathy.Endothelin-1 (ET-1) is a potent vasoconstrictive peptide originally isolated from endothelial cells, but it has since been shown to also be produced by non-endothelial cells, including renal epithelial cells and mesangial cells. ET-1 exerts its biologic actions through the activation of two different receptor isoforms. Whereas ET-A receptors (ETA) mediate vasoconstriction, mononuclear cell infiltration, and production of matrix proteins (1), ET-B receptors (ETB) on endothelial cells mediate endothelium-dependent vasorelaxation via nitric oxide (NO) and prostacyclin formation (2). Several other functions are also attributed to ETB, including regulation of renal sodium (Na ϩ ) and water excretion (3) and stimulation of ET-1 gene expression (4). Taking these biologic actions into consideration, it is not surprising to regard ET-1 as one of the important mediators for the progression of chronic renal injury (5,6). Urinary excretion of ET-1 as well as preproET-1 mRNA expression in mononuclear cells increases in patients with glomerulonephritis (7,8). Renal ET-1 levels and/or preproET-1 mRNA levels are upregulated in several experimental renal disease models of immune and nonimmune origins (5). The significance of ET-1 has been strengthened by the observation that glomerular and tubulointerstitial injury develop in preproET-1 transgenic mice despite ...

Endothelin A Receptor Blockade Reduces Diabetic Renal Injury via an Anti-Inflammatory Mechanism

“…Our data indicate that macrophage infiltration is increased in the renal cortex of diabetic rats and attenuated by treatment with ABT-627. This is consistent with reports that ET A receptor blockade suppresses macrophage infiltration in the renal cortex of rats with aldosterone-induced hypertension (25) and hypokalemia-induced renal tubulointerstitial injury (26). Previous studies have shown that macrophage infiltration precedes development of structural changes in the diabetic kidney (15,16).…”

“…ET-1 promotes macrophage infiltration in the rat kidney (25), and ET A receptor blockade suppresses macrophage infiltration in the renal cortex in nondiabetic nephropathies (26) and attenuates the increase in TGF-␤ mRNA in glomeruli from diabetic rats (27).…”

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

“…Mice were treated from 5 to 16 wk of age. The dosages of ABT-627 and A-192621 chosen were shown to be effective in previous studies (28). Mice were housed at constant temperature (21°C) and humidity (45%) on a 12-h light/dark cycle and had free access to drinking water and standard laboratory diet.…”

Altered Gene Expression Related to Glomerulogenesis and Podocyte Structure in Early Diabetic Nephropathy of db/db Mice and Its Restoration by Pioglitazone

“…Microarray gene expression. Total RNA was extracted from glomerular samples by the acid guanidine-phenol-chloroform method, using Trizol reagent (Life Technologies) (20). We essentially followed the procedures described in detail in the GeneChip expression analysis manual (Affymetrix, Santa Clara, CA).…”

“…Quantitative RT-PCR. We reverse transcribed 2.5 g of total RNA using Ready-To-Go (Amersham Pharmacia Biotech, Piscataway, NJ) (20). TaqMan real-time quantitative PCR was performed and analyzed according to the manufacturer's instructions (Applied Biosystems, Foster City, CA) (24).…”