New ATP-Sensitive Potassium Channel Opener, Iptakalim, Protects The Kidney From Damage During Experimental Hypertension

The kidney is one of the organs critically vulnerable to hypertension-related damage. Antihypertensive therapy has caused a dramatic decrease in morbidity and mortality from strokes and coronary heart disease. However, in contrast to these remarkable therapeutic achievements, the prevalence of end-stage renal disease (ESRD) associated with hypertension has increased in recent decades. Available data clearly indicate that hypertension is second only to diabetic nephropathy as a primary cause of ESRD, and accounts for 30% of ESRD. These findings imply that the treatment strategy for hypertension is not optimal in preventing renal damage. Therefore, it is important to develop new antihypertensive agents that efficiently and safely protect the kidney.ATP-sensitive potassium (Katp) channels are the main target proteins of antihypertensive agents. In vascular smooth muscle, Katp channel opening appears to induce membrane hyperpolarization and decrease intracellular Ca+ levels, thereby leading to peripheral vasodilatation and a reduction in blood pressure.Iptakalim, which belongs to a novel chemical type of KCO, possesses unique pharmacological properties. It selectively relaxes small arteries in vitro and also has selective antihypertensive activity that is more potent in the hypertensive state than in the normotensive state. As it decreases blood pressure, iptakalim also reverses hypertensive vascular remodeling and cardiac remodeling and prevents ischemic stroke. However, it is unclear whether iptakalim confers renal protection. Based on previous findings, we investigated the experimental therapeutic effectsand protective mechanism of iptakalim on hypertensive renal damage in the spontaneously hypertensive rat (SHR) model.Firstly, we investigated the experimental therapeutic effects and molecular mechanism of iptakalim on hypertensive renal damage with the SHR model. SHR (12 weeks old) were divided into four groups: control SHR group (n = 9); iptakalim-treated SHR with a dose of 1 mg kg"1 day"1 (iptakalim-1-treated group) (n = 9); iptakalim-treated SHR with a dose of 3 mg kg"1 day"1 (iptakalim-3 -treated group) (n = 9); and iptakalim-treated SHR with a dose of 9 mg kg"1 day"1 (iptakalim-9-treated group) (n = 9); WKY rats (n = 9) treated with vehicle as the normotensive control group. Iptakalim was administered by gastric lavage at doses of 1, 3, or 9 mg kg~! day"1 for 12 weeks. Iptakalim effectively decreased systolic blood pressure, ameliorated pathological changes in the glomerular filtration membrane and the glomerular and renal interstitia, reversed afferent arteriolar remodeling, decreased proteinuria, and improved renal function. Iptakalim simultaneously decreased blood and intrarenal concentrations of ET-1 and transforming growth factor (TGF)-pi. These findings indicate that iptakalim reduces blood pressure and reverses hypertensive renal damage in SHR, accompanied by a decrease in the circulation and intrarenal activity of the ET-1 system and the concentration TGF-Pi.Secondly, we used morphological measurements to investigate the effects of iptakalim on the structure of the afferent arteriole, arcuate artery, and interlobular artery and examined changes in the protein component of the arterial wall using immunohistochemistry. Iptakalim reduced the luminal diameter of the afferent arteriole, arcuate artery, and interlobular artery, which are significantly larger in SHR. It also reduced the wall/lumen ratio and wall thickness of the afferent arteriole, arcuate artery, and interlobular artery, which are significantly greater in SHR. Iptakalim also decreased the expression of CollagenlV and fibronectin proteins in the arcuate artery and interlobular artery in SHR. This indicates thatiptakalim protects the kidney from hypertensive damage partly by decreasing the protein of component of the arterial wall, thus inhibiting renal arteriolar remodeling.Thirdly, we investigated the effects of iptakalim on Katp mRNA expression in SHR kidney. Transcript levels for SUR2, Kir6.1, and Kir 1.1 were elevated in SHR kidney. Following long-term treatment with iptakalim, Kir6.1 and Kirl.l mRNA expression was significantly reduced in the SHR kidney compared with the untreated controls. SUR2 mRNA expression did not change. Therefore, the renoprotection afforded by iptakalim may involve the regulation of Kir6.1 and Kirl.l gene expression.Finally, the effects of iptakalim on extracellular matrix degradation were tested in SHR kidneys. The expression of MMP-9 mRNA and protein was down-regulated, and that of TGF-(3i, TIMP-1, and Collagen-IV was up-regulated. After long-term treatment with iptakalim, the expression of MMP-9 mRNA and protein was up-regulated, and that of TGF-Pi, TIMP-1, and Col-IV was down-regulated in the SHR kidney compared with the untreated controls. This suggests that iptakalim protects the kidney from hypertensive damage partly by inhibiting TGF-pi expression and regulating MMP-9/TIMP-1 expression in renal tissue. This may be an important renoprotective mechanism of iptakalim in hypertension.In summary, our study indicates that, in the SHR model, iptakalim not only effectively reduced blood pressure, but also ameliorated the pathological changes in the glomerular filtration membrane and the glomerular and renal interstitia, reversed renal arteriolar remodeling, decreased proteinuria, and improved renal function. Furthermore, long-term antihypertensive therapy with iptakalim decreased the circulating and intrarenal concentrations of ET-1 and TGF-pi, down-regulated the elevated expression of ET-1, ECE-1, TGF-pl, and the Katp channel subunits, Kir6.1 and Kirl.l, and corrected the MMP-9/TIMP-1 imbalance...