The Effect of Chloroquine on Renal Function and Vasopressin Secretion: A Nitric Oxide-Dependent Effect

Ahmed, Mohamed H.; Ashton, Nick; Balment, R. J.

doi:10.1124/jpet.102.042523

Cited by 29 publications

(39 citation statements)

References 26 publications

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“…It has been demonstrated that CQ administration results in NO production by the endothelium as well as expression of endothelial nitric oxide synthase in some cell types, leading to renal failure and oxidative distress. [6][7][8] We also found that CQ stimulated the expression of iNOS in DCs WT (Figure 1b). Interestingly, the expression of IDO, an immunomodulatory enzyme, was also elevated, and this effect was observed both in CQ-DCs WT and CQ-DC iNOS 2/2 ( Figure 1b).…”

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confidence: 63%

Nitric oxide plays a key role in the suppressive activity of tolerogenic dendritic cells

et al. 2014

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Tolerogenic dendritic cells (DCs) are widely studied for their possible use in the treatment of inflammatory disorders, such as autoimmune diseases. One of the obstacles for the use of this cell-based therapy is the characterization of drugs that are able to modulate DCs. We have previously shown that chloroquine (CQ), an antimalarial agent, has the ability to modulate DCs towards a tolerogenic phenotype. 1 These tolerogenic DCs are able to suppress the development of experimental autoimmune encephalomyelitis (EAE), a T cell-driven mouse model of human multiple sclerosis. In addition, several studies have proposed that nitric oxide (NO) plays a major role in the differentiation of regulatory T cells (Tregs) and the suppression of Th1/Th17 cells. 2,3 However, little is known about the role of DC-derived NO in the modulation of inflammatory autoimmune responses. Thus, we aimed to evaluate whether NO plays a role in the tolerogenic activity of CQ-treated DCs (CQDCs). We found that CQ induces DC production of NO and expression of indoleamine 2,3-dioxygenase (IDO), as well as inducible nitric oxide synthase (iNOS). In addition, CQ-DCs stimulated the differentiation of Tregs at the expense of Th1/ Th17 cells. On the other hand, iNOS 2/2 DCs did not acquire a tolerogenic phenotype following CQ treatment. Rather, CQDCs iNOS2/2 stimulated the differentiation of Th1/Th17 cells as well as Tregs. In a therapeutic approach, CQ-DCs iNOS2/2 were unable to suppress the development of EAE. Gene expression analyses of central nervous system (CNS) tissue from mice that received CQ-DCs iNOS2/2 showed an increased expression of inflammatory modulators compared with mice that received CQ-DCs WT . In this work, we show that NO is an important factor in the modulatory activity of tolerogenic dendritic cells.DCs are antigen-presenting cells that can dictate the course of the immune response via the modulation and activation of naive T cells. DC modulation is a possible approach to address the immunosuppression that is often caused by tumors 4 and the exacerbated immune response observed in autoimmune diseases. 5 Multiple sclerosis, one such autoimmune disease, is a debilitating condition that affects the CNS. Studies in EAE, an experimental mouse model of multiple sclerosis, have found that much of the immunological etiology of the disease development is due to the activity of Th1/Th17 cells, and these studies have found that NO plays a major role in disease progression. 2 To verify whether NO is involved in the modulatory activity of tolerogenic DCs, we generated DCs from bone marrow precursors obtained from wild-type (DCs WT ) and iNOS 2/2 (DCs iNOS2/2 ) mice and treated these DCs with CQ or vehicle (PBS-DCs WT ). All protocols involving laboratory animals were approved by the institutional committee (protocol no. 2687-1). NO measurements revealed that CQ treatment induced DCs WT to produce large amounts of NO in an iNOS-dependent manner (Figure 1a). It has been demonstrated that CQ administration results in NO production by the endot...

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confidence: 63%

Nitric oxide plays a key role in the suppressive activity of tolerogenic dendritic cells

et al. 2014

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“…Briefly, animals were anesthetized with Intraval (100 mg/kg body wt, thiopentone sodium BP; Rhone-Poulenc Rorer Limited, Nenagh, Co Tipperary, Ireland), and cannulae were inserted into an external jugular vein, carotid artery, and the bladder. Euvolemic fluid replacement of spontaneous urine output was achieved using a servocontrolled fluid replacement system, as described previously (21). Briefly, urine flow rate (UV), determined gravimetrically, is transmitted to an adjustable pump via a computer.…”

Section: Methodsmentioning

confidence: 99%

“…Male OC (4 wk, n ϭ 5 from five litters; 8 wk, n ϭ 9 from six litters) and OD (4 wk, n ϭ 5 from five litters; 8 wk, n ϭ 6 from five litters) were prepared for renal function study as described previously (21). Briefly, animals were anesthetized with Intraval (100 mg/kg body wt, thiopentone sodium BP; Rhone-Poulenc Rorer Limited, Nenagh, Co Tipperary, Ireland), and cannulae were inserted into an external jugular vein, carotid artery, and the bladder.…”

Section: Methodsmentioning

confidence: 99%

Increased Renal Tubular Reabsorption of Calcium and Magnesium by the Offspring of Diabetic Rat Pregnancy

et al. 2005

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Diabetic pregnancy has a marked influence on offspring calcium and magnesium homeostasis. Urinary excretion of calcium and magnesium is reduced, yet offspring of diabetic pregnancy exhibit hypomagnesemia and hypocalcemia. The aim of this study was to measure renal hemodynamic and tubular function in the offspring of diabetic (OD) and control, nondiabetic (OC) rats at 4 and 8 wk of age to determine the glomerular and tubular mechanisms through which renal calcium and magnesium handling are programmed in utero. The fraction of filtered calcium that was excreted was significantly lower in OD at both 4 and 8 wk of age [8 wk: OC (n ϭ 6), 11.8 Ϯ 2.9 versus OD (n ϭ 5), 4.3 Ϯ 0.6%; p Ͻ 0.05] and that of magnesium was lower at 8 wk of age [OC (n ϭ 6), 42.4 Ϯ 7.5 versus OD (n ϭ 5), 13.0 Ϯ 1.7%; p Ͻ 0.01]. This increased reabsorption occurred despite an elevated GFR in OD. These findings clearly indicate that tubular reabsorptive mechanisms for calcium and magnesium are increased markedly in OD. Serum PTH concentration was reduced in 8-wk-old OD [OC (n ϭ 7), 539.4 Ϯ 142.1 versus OD (n ϭ 9), 174.3 Ϯ 69.4 pg/ml; p Ͻ 0.05], consistent with previous reports in human infants. Taken together, these observations suggest that the basis for the altered renal magnesium and calcium handling in OD involves increased tubular transport activity and possibly increased sensitivity of these mechanisms to PTH. Diabetic pregnancy has a marked impact on maternal calcium and magnesium homeostasis in both humans and rats. Hypomagnesemia has been widely reported in human diabetic pregnancy (1-3), and diabetic pregnant rats display a marked increase in urinary magnesium excretion (4,5). A reduction in third-trimester plasma calcium concentration has been observed in human diabetic pregnancy in one study (3), but the majority of studies have found no difference in calcium concentrations between normal and diabetic pregnancies. However, in the diabetic rat, pregnancy is associated with marked increases in urinary calcium (4,5) and hypocalcemia in some (4) but not all studies (6).These changes in maternal divalent ion handling have a profound impact on the developing fetus. Human offspring of diabetic pregnancy exhibit hypomagnesemia and hypocalcemia as neonates (2,7-9). In the rat, renal handling of calcium and magnesium is also altered in the offspring of streptozotocin (STZ)-treated diabetic rats (OD). We recently reported that OD retain both calcium and magnesium as neonates and that this continues into adulthood (10). These changes in divalent ion homeostasis also occur in conjunction with changes in bone structure. Human offspring of diabetic pregnancy are susceptible to congenital malformations, including skeletal abnormalities (11), and have lower bone mineral content (12). Reduced bone mineral content and abnormal skeletal development have also been observed in the offspring of STZ-treated diabetic rat mothers (13,14). We recently extended these observations and showed that offspring of STZ-treated diabetic rats have reduced trabecular and ...

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“…The TLRs that recognize bacterial and viral nucleic acids (3,(7)(8)(9) are found in the endosomal compartment (4,26) and appear to be trafficking between endosomes and lysosomes (1,14,29). When trafficking and/or acidification is disrupted by chloroquine or bafilomycin A1, TLR signaling is inhibited (1,14,30,32,37).…”

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confidence: 99%

Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury

Yasuda¹,

Leelahavanichkul²,

Tsunoda³

et al. 2008

American Journal of Physiology-Renal Physiology

175

159

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The Effect of Chloroquine on Renal Function and Vasopressin Secretion: A Nitric Oxide-Dependent Effect

Cited by 29 publications

References 26 publications

Nitric oxide plays a key role in the suppressive activity of tolerogenic dendritic cells

Nitric oxide plays a key role in the suppressive activity of tolerogenic dendritic cells

Increased Renal Tubular Reabsorption of Calcium and Magnesium by the Offspring of Diabetic Rat Pregnancy

Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury

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