• Journal of Yeungnam Medical Science
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• v.36 no.1
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• pp.26-35
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• 2019

Background: Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice. Methods: Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase ${\alpha}$ ($G6Pase-{\alpha}$), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ${\zeta}$ ($PKC{\zeta}$) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice. Results: Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a $40{\mu}M$ concentration without a change in $G6Pase-{\alpha}$ expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 ($p-IRS-1-Ser^{302}$) and decreased $p-IRS-1-Tyr^{632}$ dose-dependently. Telmisartan dose-dependently increased $p-PKC{\zeta}-Thr^{410}$ which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative $PKC{\zeta}$ significantly attenuated telmisartan-induced HGP and $p-IRS-1-Ser^{302}$ and -inhibited $p-IRS-1-Tyr^{632}$. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased $p-IRS-1-Ser^{302}$ and decreased $p-IRS-1-Tyr^{632}$, which was accompanied by an increase in $p-PKC{\zeta}-Thr^{410}$. Conclusion: These results suggest that telmisartan increases HGP by inducing $p-PKC{\zeta}-Thr^{410}$ that increases $p-IRS-1-Ser^{302}$ and decreases $p-IRS-1-Tyr^{632}$ in a $PPAR{\gamma}$-independent manner

• Childhood Kidney Diseases
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• v.14 no.1
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• pp.1-9
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• 2010

Slowing the progression of chronic kidney disease is much more important in children and adolescents with a relatively longer remaining life span. A practical way to assess the rate of progression of chronic kidney disease is to measure the change of GFR estimated by formulae. To slow the progression, hypertension and proteinuria have to be controlled strictly, and hypoplastic anemia must be treated with erythropoietin. If not contraindicated, ACE inhibitor or angiotensin receptor blocker is recommended with monitoring of the side effects. Trials to slow the progression should be commenced as soon as the chronic kidney disease is confirmed and needs to be continued until renal transplantation as long as residual renal function remains. An online system, the Korean Pediatric Chronic Kidney Disease Registry (http://pedcrf.or.kr/), provides tools that are useful in evaluation and management of the children and adolescents with chronic kidney diseases.

• Childhood Kidney Diseases
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• v.25 no.1
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• pp.29-34
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• 2021

C3 glomerulonephritis (C3GN), a rare condition associated with dysregulation of the alternative pathway of the complement system, is histopathologically characterized by isolated or dominant C3 deposition in the renal glomeruli. We report a case of C3GN associated with anti-complement factor H (CFH) autoantibodies and CHF-related protein deficiency in an adolescent male. A 16-year-old adolescent male was admitted to a hospital with a 1-month history of generalized edema prior to presentation. Persistent microscopic hematuria and low serum C3 levels were incidentally detected at 7 and 10 years of age, respectively. Laboratory test results revealed hypoalbuminemia, nephrotic-range proteinuria, microscopic hematuria, and normal serum creatinine levels. The serum C3 and C4 levels were 17 mg/dL (normal 80-150 mg/dL) and 22 mg/mL (17-40 mg/mL), respectively. Renal biopsy showed typical features of C3GN. Further investigations revealed positive results on plasma anti-CFH autoantibody testing and a homozygous deletion of CFHR1 and CFHR3, which encode CFH-related proteins 1 and 3, respectively. Proteinuria persisted despite treatment with intravenous methylprednisolone, mycophenolate mofetil, and angiotensin-receptor blocker; however, his renal function remained stable. In conclusion, anti-CFH autoantibodies serve as important contributors to C3GN. This is the first case report that describes C3GN in an adolescent Korean male with anti-CFH autoantibodies and homozygous CFHR1 and CFHR3 deletion.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.4
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• pp.241-248
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• 2010

The present sutdy aimed to determine whether olmesartan, an angiotensin II (Ang II) type 1 ($AT_1$) receptor blocker, can influence the CA release from the isolated perfused model of the rat adrenal medulla. Olmesartan ($5{\sim}50{\mu}M$) perfused into an adrenal vein for 90 min produced dose- and time-dependent inhibition of the CA secretory responses evoked by ACh (5.32 mM), high $K^+$ (56 mM, a direct membrane-depolarizer), DMPP (100 ${\mu}M$) and McN-A-343 (100 ${\mu}M$). Olmesartan did not affect basal CA secretion. Also, in adrenal glands loaded with olmesartan (15 ${\mu}M$), the CA secretory responses evoked by Bay-K-8644 (10 ${\mu}M$, an activator of voltage-dependent L-type $Ca^{2+}$ channels), cyclopiazonic acid (10 ${\mu}M$, an inhibitor of cytoplasmic $Ca^{2+}$-ATPase), veratridine (100 ${\mu}M$, an activator of voltage-dependent $Na^+$ channels), and Ang II (100 nM) were markedly inhibited. However, at high concentrations ($150{\sim}300{\mu}M$), olmesartan rather enhanced the ACh-evoked CA secretion. Taken together, these results show that olmesartan at low concentrations inhibits the CA secretion evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by direct membrane depolarization from the rat adrenal medulla, but at high concentrations it rather potentiates the ACh-evoked CA secretion. It seems that olmesartan has a dual action, acting as both agonist and antagonist at nicotinic receptors of the isolated perfused rat adrenal medulla, which might be dependent on the concentration. It is also thought that this inhibitory effect of olmesartan may be mediated by blocking the influx of both $Na^+$ and $Ca^{2+}$ into the rat adrenomedullary chromaffin cells as well as by inhibiting the $Ca^{2+}$ release from the cytoplasmic calcium store, which is thought to be relevant to the $AT_1$ receptor blockade, in addition to its enhancement on the CA secreton.

• Korean Journal of Clinical Pharmacy
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• v.21 no.2
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• pp.122-130
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• 2011

Objective: Although recombinant human erythropoietin (rhEPO) has revolutionized the treatment of anemia in chronic kidney disease (CKD) receiving hemodialysis (HD) with no need of blood transfusion, some patients have a blunted or appear to be resistant to rhEPO. There is a controversy in the causes of rhEPO resistance in maintenance HD patients with anemia. This study is to examine current anemia treatment outcomes and the factors influencing the rhEPO responsiveness in HD patient with CKD. Methods: The clinical parameters or factors relating to erythrompoietin treatment outcomes and erythropoietin responsiveness were collected from the HD patients in two large dialysis centers for three months. The collected paramenters included serum iron, total iron biding capacity (TIBC), transferrin saturation rate, ferritin, albumin, intact PTH, C-reactive protein (CRP), nPCR and medications such as an angiotensin converting enzyme inhbitor, an angiotension II receptor blocker and an HMG-CoA reductase inhibitor (HMG-CoA RI). The data were analyzed to examine the degree of acheiveing the anemia treatment goal and factors relating to ERI. Results: Among total 111 patients, 42 (42.3%) and 47 (37.8%) patients achieved the target Hct and Hb based on the Health Insurance Review and Assessment Services (HIRA) reimbursement criteria. In the higher ERI group (upper quartile), the patients had higher CRP levels (0.5 mg/dl) (p=0.0096), and lower TIBC score (<$240{\mu}g/dl$) (p=0.0027), and less patients were taking HMG-CoA RI (p=0.0019). Male patients (p=0.0204), patients with high TIBC score ($R^2$=0.084, p=0.0021) and patients taking HMG-CoA RI (p=0.0052) required to administer less dose of rhEPO meaning higher erythropoietin responsiveness. Conclusion: Less than 50% of CKD patients were achieving the goals of anemia by erythropoietin administration in large hospitals in Korea even though the goals were lower than those of NKF-K/DOQI practice guideline. The factors influencing ERI were sex, TIBC and HMG-CoA RI administration status, and neither an ACEI nor an ARB did not influence ERI.

• Journal of Chest Surgery
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• v.40 no.8
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• pp.582-586
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• 2007

A 48-year old male patient visited our hospital with uncontrolled hypertension and pair of the left leg. CT angiography shows atherosclerotic occlusion of both renal artery orifices and the left common iliac artery. Despite of medical treatment for 2 months, the clinical condition of the patient worsened. We performed the surgical revascularization with both renal arteries and aorto-left femoral artery bypass with using an 8 mm artificial vascular graft. He lived well without hypertension with using only angiotensin receptor blocker and an anticoagulant for 10 postoperative months. Using surgical revascularization for renovascular hypertension has decreased due to the development of intervention technology and medication, but this surgery is indicated in cases of renovascular hypertension with extensive atherosclerotic lesions. We report here on a case of surgical revacularization for medically Intractable atherosclerotic renovascular hypertension together with left common iliac artery occlusion.