Dual effect of insulin-like growth factor on the apical 70-pS K channel in the thick ascending limb of rat kidney
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. AJP Cell Physiology
(Impact Factor: 3.78).
07/2004; 286(6):C1258-63. DOI: 10.1152/ajpcell.00441.2003
We used the patch-clamp technique to study the effect of insulin-like growth factor I (IGF-I) on the apical 70-pS K channel in the isolated thick ascending limb (TAL) of the rat kidney. The isolated TAL was cut open to gain access to the apical membrane. Addition of 25 nM IGF-I stimulates the apical 70-pS K channel and increases channel activity, defined by the product of channel open probability and channel number, from 0.31 to 1.21. The stimulatory effect of IGF-I is not mediated by nitric oxide- or protein tyrosine phosphatase-dependent mechanisms, because inhibition of nitric oxide synthase or blocking protein tyrosine phosphatase did not abolish the stimulatory effect of IGF-I on the 70-pS K channel. In contrast, inhibition of mitogen-activated protein (MAP) kinase with PD-98059 or U0126 abolished the stimulatory effect of IGF-I. This suggests that MAP kinase is responsible for mediating the effect of IGF-I on the apical K channels. Moreover, the effect of IGF-I on the apical 70-pS K channel is biphasic because high concentrations (>200 nM) inhibit apical 70-pS K channels. Application of 400 nM IGF-I decreased channel activity from 1.45 to 0.2. The inhibitory effect of IGF-I is not blocked by calphostin C (an inhibitor of PKC), but inhibition of protein tyrosine kinase with herbimycin A abolished the IGF-induced inhibition. We conclude that IGF-I has a dual effect on the apical 70-pS K channel in the TAL: low concentrations of IGF-I stimulate, whereas high concentrations inhibit the channel activity. The stimulatory effect of IGF-I is mediated by a MAP kinase-dependent pathway, whereas the inhibitory effect is the result of stimulation of protein tyrosine kinase.
Available from: jasn.asnjournals.org
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ABSTRACT: Insulin resistance is frequently associated with hypertension, but the mechanism underlying this association remains speculative. Although insulin is known to modify renal tubular functions, little is known about roles of insulin receptor substrates (IRS) in the renal insulin actions. For clarifying these issues, the effects of insulin on the rate of bicarbonate absorption (JHCO3-) were compared in isolated renal proximal tubules from wild-type, IRS1-deficient (IRS1-/-), and IRS2-deficient (IRS2-/-) mice. In wild-type mice, physiologic concentrations of insulin significantly increased JHCO3-. This stimulation was completely inhibited by wortmannin and LY-294002, indicating that the phosphatidylinositol 3-kinase pathway mediates the insulin action. The stimulatory effect of insulin on JHCO3- was completely preserved in IRS1-/- mice but was significantly attenuated in IRS2-/- mice. Similarly, insulin-induced Akt phosphorylation was preserved in IRS1-/- mice but was markedly attenuated in IRS2-/- mice. Furthermore, insulin-induced tyrosine phosphorylation of IRS2 was more prominent than that of IRS1. These results indicate that IRS2 plays a major role in the stimulation of renal proximal absorption by insulin. Because defects at the level of IRS1 may underlie at least some forms of insulin resistance, sodium retention, facilitated by hyperinsulinemia through the IRS1-independent pathway, could be an important factor in pathogenesis of hypertension in insulin resistance.
Journal of the American Society of Nephrology 09/2005; 16(8):2288-95. DOI:10.1681/ASN.2005020193 · 9.34 Impact Factor
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ABSTRACT: Recent work has shown that female animals are more resistant to ischemic acute renal failure (ARF) than male animals. The mechanism underlying the gender difference is unclear. Moreover, whether the gender difference holds true for ARF induced by other insults is unknown. This study sought to determine the gender differences in ischemic and nephrotoxic ARF.
Gender differences were tested in two experimental models of ARF. For ischemic ARF, bilateral clamping of renal pedicles was conducted in C57BL/6 and 129/Sv mice followed by reperfusion. For nephrotoxic ARF, cisplatin was administered to the animals. Renal function, tissue damage, animal survival, and renal cell apoptosis were examined.
Ischemic ARF was significantly ameliorated in female mice, as shown by lower serum creatinine and blood urea nitrogen (BUN). Female mice also showed better renal histology, less apoptosis and caspase activation, and a much better survival rate than male mice following ischemic insult. On the contrary, female mice were more sensitive to cisplatin-induced ARF. In these animals, BUN increased at day 1 following cisplatin injection, while in males BUN increases were not shown until day 3. Higher levels of serum creatinine were also recorded in female mice. Renal histology showed severer necrotic tubular damage in females, although apoptosis and caspase activation appeared similar in both genders. Consistently, male mice survived better than females in the nephrotoxic model.
While female mice were resistant to ischemic ARF, they appeared more sensitive to cisplatin-induced ARF. Investigation of the gender differences at the cellular and molecular levels might provide a new area for mechanistic study of ARF.
American Journal of Nephrology 09/2005; 25(5):491-9. DOI:10.1159/000088171 · 2.67 Impact Factor
Available from: Erik M Schwiebert
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ABSTRACT: In this review, we focus on two attributes of P2X receptor channel function, one essential and one novel. First, we propose that P2X receptors are extracellular sensors as well as receptors and ion channels. In particular, the large extracellular domain (that comprises 70% of the molecular mass of the receptor channel protein) lends itself to be a cellular sensor. Moreover, its exquisite sensitivity to extracellular pH, ionic strength, and multiple ligands evokes the function of a sensor. Second, we propose that P2X receptors are extracellular zinc receptors as well as receptors for nucleotides. We provide novel data in multiple publications and illustrative data in this invited review to suggest that zinc triggers ATP-independent activation of P2X receptor channel function. In this light, P2X receptors are the cellular site of integration between autocrine and paracrine zinc signaling and autocrine and paracrine purinergic signaling. P2X receptors may sense changes in these ligands as well as in extracellular pH and ionic strength and transduce these sensations via calcium and/or sodium entry and changes in membrane potential.
Purinergic Signalling 01/2006; 1(4):299-310. DOI:10.1007/s11302-005-0777-7 · 3.89 Impact Factor
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