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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The existence of a hepatorenal link is suggested by several pathophysiological observations (indirect actions of glucagon on the kidney, hepatorenal syndrome), but the nature of this link remains unidentified. We propose that extracellular circulating cyclic AMP could be this link. Cyclic AMP (cAMP) is the intracellular second messenger of glucagon (G) action in the liver, and this organ is known to release cAMP in the blood in relatively large amounts after G administration. On the other hand, the proximal tubule (mainly the pars recta) is known to take up cAMP through the organic acid transport system. We observed that the glucagon-induced rise in phosphate excretion, which requires supraphysiologic concentration of G, was significantly correlated with the simultaneous rise in plasma cAMP and could be mimiked by i.v. infusion of cAMP alone. Moreover, we showed that a significant hyperfiltration (similar to that induced by supraphysiologic G) can be observed if cAMP (mimicking G-induced hepatic release) is coinfused with a much lower, physiologic, amount of G. Taken together, these observations suggest that: (1) cAMP is a hepatorenal link and that plasma cAMP permanently influences the intensity of reabsorption in the pars recta of the proximal tubule; and (2) that cAMP participates, in conjunction with G, to control GFR. Insulin is known to exert an inhibitory influence on G-induced cAMP release by the liver and will thus weaken the indirect (cAMP-mediated) influence of G on renal function. This "pancreato-hepatorenal cascade" may explain the natriuretic effects of G and antinatriuretic effects of insulin, and probably contributes to disturbances observed in some pathophysiological situations such as the edema of liver cirrhosis or hyperfiltration of diabetes.
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PMID:Plasma cAMP: a hepatorenal link influencing proximal reabsorption and renal hemodynamics? 918 5

There have been many reports of increased Na-H exchange (NHE) activity in the peripheral blood cells (erythrocytes, lymphocytes and platelets) of patients with diabetes mellitus compared to nondiabetic controls. This raised NHE activity has been hypothesized to reflect increased NHE activity in kidney and vascular smooth muscle. Raised NHE activity in these tissues could play a pathophysiological role in mediating hypertension, vascular smooth muscle cell proliferation and progressive renal impairment. It is now known that there are at least five NHE isoforms, but a specific study examining expression of NHE isoforms in peripheral blood cells has not been reported. This study used specific antisera to NHE isoforms 1, 3 and 4 to examine NHE expression by immunoblot analysis. Erythrocyte, lymphocyte and platelet membranes from both rabbit and rat were separated by standard methods. A monoclonal antibody to NHE-1 reacted with a 100-110 kDa band in rabbit and rat platelets and lymphocytes (identical to that observed in basolateral-enriched renal cortical vesicles) and a 100 kDa band in rabbit and rat erythrocytes. In both species, the intensity of the staining was greatest in platelet membranes. A polyclonal antibody to NHE-3, the isoform present on the apical membranes of renal proximal tubule, showed no evidence of staining in any of the peripheral blood cell preparations. Similarly there was no evidence of expression of NHE-4 in the peripheral blood cell preparations. Peripheral blood cells express NHE-1, which likely accounts for amiloride-sensitive Na-H exchange in these cells, playing a role in cell volume and pH regulation. However, there is no evidence that there is expression of NHE-3 or NHE-4 in peripheral blood cells. These data have implications for studies in hypertension and diabetes mellitus which measure peripheral blood cell Na-H exchange and hypothesize regarding a direct pathophysiological role for this increased activity.
Exp Clin Endocrinol Diabetes 1997
PMID:Sodium-hydrogen exchange isoform expression in blood cells: implications for studies in diabetes mellitus. 928 35

We review some of the effects that insulin exerts on glomerular and tubular functions. In healthy subjects, insulin has little or no effect on renal hemodynamics, glomerular filtration rate, or permeability to albumin. In patients with noninsulin-dependent diabetes, hyperinsulinemia selectively increases urinary albumin excretion. In vivo, euglycemic hyperinsulinemia is associated with reduced urinary sodium excretion both under conditions of forced and normal diuresis. Whether the principal site of this action is the proximal or distal tubule remains somewhat controversial. The effect, however, is not mediated by insulin-induced hypokalemia and antikaliuresis, as it is still observed when plasma potassium concentrations and urinary potassium excretion are maintained. Hyperglycemia potentiates insulin antinatriuresis through an effect on the proximal tubule (sodium-glucose cotransport). Insulin antinatriuresis is accompanied by a reduction in the urinary excretion of uric acid. Both the antinatriuretic and antiuricosuric effect of insulin are preserved in states of insulin resistance of glucose metabolism (obesity, diabetes, essential hypertension). Thus, in insulin resistant individuals compensatory hyperinsulinemia imposes a chronic antinatriuretic and antiuricosuric pressure on the kidney. This may provide an explantation for the clustering of insulin resistance with hypertension and hyperuricemia.
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PMID:Renal effects of insulin in man. 937 25

Renal acid excretion and proximal and distal nephron acidification were evaluated 20 days after induction of diabetes, in rats, by intraperitoneal injection of streptozotocin (45 mg/kg). Titratable acidity in urine was measured by microtitration and ammonium excretion (NH4+) by spectrophotometry. Proximal tubular acidification was evaluated by the kinetics of reabsorption of perfused HCO3-. Distal nephron acidification was evaluated by measuring urine - blood pCO2 differences under alkaline overload. The net acid excretion (titratable acidity + NH4+ - HCO3-) was higher (p < 0.001) in diabetic rats (9.82+/-0.65 micromol/min/kg, n = 26) than in the control group (6.34+/-0.14, n = 24). Proximal HCO3- reabsorption was also higher (p < 0.001) in diabetic rats (8.38+/-0.11 nmol/cm2/s, n = 12) than in the control group (2.30+/-0.10, n = 22); however, evaluation of distal nephron H+ secretion by urine - blood pCO2 methodology was similar in both groups. We concluded that in rats with induced diabetes mellitus there is an increased rate of proximal HCO3- reabsorption, possibly effected by a higher density of Na+/H+ antiporter in the luminal membrane of the proximal tubule and by an increased proton-motive force of the H+ secretory mechanism. The higher rates of H+ secretion generate lower stationary proximal luminal pH and probably maintain the blood pH within the physiological range.
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PMID:Alterations of the renal handling of H+ in diabetic rats. 939 31

This study investigated the effect of chronic hypertonicity on the OKP cell Na/H antiporter, encoded by Na/H exchanger 3 (NHE3). Chronic (48 h) increases in extracellular glucose, mannitol, or raffinose concentration caused a significant increase in Na/H antiporter activity, while increases in urea concentration were without effect. This effect was seen with changes in osmolality of only 20 mOsm/liter, a magnitude that is observed clinically in poorly controlled diabetes mellitus. Increases in mannitol concentration acutely inhibited and chronically stimulated Na/H antiporter activity. The increase in Na/H antiporter activity induced by hypertonic incubation was resistant to 10(-7) and 5 x 10(-6) M but inhibited by 10(-4) M ethylisopropyl amiloride, consistent with regulation of NHE3. In addition, hypertonicity increased total cellular and plasma membrane NHE3 protein abundance twofold, with only a small increase in NHE3 mRNA abundance. We conclude that chronic pathophysiologically relevant increases in tonicity lead to increases in NHE3 protein abundance and activity. This may be responsible for increased proximal tubule apical membrane Na/H antiporter activity in poorly controlled diabetes mellitus, which could then contribute to hypertension, glomerular hyperfiltration and diabetic nephropathy.
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PMID:Chronic hyperosmolality increases NHE3 activity in OKP cells. 942 79

Advanced glycation end products (AGEs) generated through the Maillard reaction significantly alter protein characteristics. Their accumulation has been incriminated in tissue injury associated with aging, diabetes, and renal failure. However, little is known about their clearance from the body. The present study delineates the catabolic pathway of a well-defined AGE product, pentosidine. Synthesized pentosidine given intravenously in rats with normal renal function was rapidly eliminated from the circulation through glomerular filtration, but was undetectable in the urine by chemical analysis. Immunohistochemistry with anti-pentosidine antibody disclosed that pentosidine accumulated transiently in the proximal renal tubule one hour after its administration, but had disappeared from the kidney at 24 hours. After an intravenous load of radiolabeled pentosidine, radioactivity peaked in the kidney at one hour and subsequently decreased, whereas it rose progressively in the urine. Over 80% of the radioactivity was recovered in the 72-hour collected urine. However, only 20% of urine radioactivity was associated with intact pentosidine chemically or immunochemically. In gentamicin-treated rats with tubular dysfunction, up to 30% of the pentosidine load was recovered as intact pentosidine in the urine. The present study suggests that free pentosidine (and possibly other AGEs) is filtered by renal glomeruli, reabsorbed in the proximal tubule where it is degraded or modified, and eventually excreted in the urine. Kidney thus plays a key role in pentosidine disposal.
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PMID:Renal catabolism of advanced glycation end products: the fate of pentosidine. 946 Nov 1

A role of renal angiotensin-converting enzyme (ACE) in diabetic nephropathy has been suggested. Immunohistochemical localization of ACE was studied in 20 non-insulin-dependent diabetes mellitus patients with diabetic nephropathy and 17 healthy kidney transplant donors, with ACE gene insertion/deletion (I/D) polymorphism also examined in the latter. Immunohistochemical studies indicated that ACE staining was significantly (P < 0.01) enhanced in glomeruli and slightly decreased in proximal tubules in diabetic patients. Glomeruli positive for ACE immunostaining were observed in 23.5% of the healthy subjects and in 80% of the diabetic patients. All patients with nodular lesions had ACE-positive glomeruli and showed significantly (P < 0.01) more intense glomerular ACE immunostaining than patients without nodular lesions. Among healthy controls, subjects with the DD genotype had ACE-positive glomeruli more frequently and tended to show slightly increased intensity on proximal tubule ACE immunostaining compared with subjects with other genotypes. These observations suggest that increased ACE localization in glomeruli is likely to be one of the factors in the increased renin-angiotensin system activity in glomeruli in patients with diabetic nephropathy. There is a possibility that ACE gene I/D polymorphism may be related to renal ACE immunohistochemical localization.
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PMID:Renal ACE immunohistochemical localization in NIDDM patients with nephropathy. 946 1

We previously demonstrated an increased sensitivity of the renal vasculature to adenosine (ADO) mediated via ADO A1 receptors in streptozotocin (STZ) diabetic rats. Because ADO stimulates P(i) reabsorption in the proximal tubule, the present study was performed to determine whether the sensitivity of the renal tubular system to the antiphosphaturic effect of ADO is enhanced in STZ rats. Clearance studies were performed, and ADO was infused into the renal interstitium via implanted matrices in STZ- and control (Con) rats to mimic the effects of endogenous ADO. Renal phosphate excretion was significantly increased in STZ rats (0.75 +/- 0.05 mumol/24 h) compared with Con rats (0.35 +/- 0.08 mumol/24 h), and fractional phosphate excretion (FEPi) tended to be higher in STZ rats (34.8 +/- 4.1%) than in Con rats (26.7 +/- 2.2%). Renal interstitial ADO infusion (5 mumol/h) was significantly more antiphosphaturic in STZ rats (FEPi decreased by 2.90 +/- 1.6%; P > 0.05), in which ADO only tended to decrease FEPi. To determine the role of ADO A1 receptors on P(i) excretion, the selective ADO A1 receptor blocker 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was infused into the renal interstitium. DPCPX increased FEPi by 4.3 +/- 1.2% (P < 0.05) in the presence and 7.1 +/- 3.9% (P < 0.05) in the absence of ADO infusion in Con rats but had no effect on FEPi in STZ rats. In conclusion, STZ-diabetes mellitus enhances the antiphosphaturic effect of ADO by mechanisms unrelated to ADO A1 receptor stimulation.
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PMID:Effect of renal interstitial adenosine infusion on phosphate excretion in diabetes mellitus rats. 964 34

The potential role of hepatocyte growth factor (HGF) in regulating extracellular matrix in mouse mesangial cells (MMC) was evaluated. Functional HGF receptors were deed in MMC by HGF-induced extracellular acidification, a response that was inhibited by the HGF inhibitor HGF/NK2, a splice variant expressing the N-terminal domain through the second kringle domain HGF also increased fibronectin and collagen alpha1 (IV) mRNA levels in these cells; the increases were associated with a concentration-dependent increase in transcriptional activity of the collagen alpha1 (IV) gene. HGF also stimulated fibronectin and collagen alpha1 (IV) mRNA levels in primary rabbit proximal tubule epithelial cells To evaluate the potential consequences of chronic elevation of HGF on renal fuction, HGF was administered continuously for 18 days to normal and diabetic C57BLKS/J lepr(db) mice. In the diabetic mice, HGF reduced creatinine clearance and increased microalbuminuria, indicating that chronic exposure to HGF impairs renal function. Thus, chronically elevated HGF may contribute to the progression of chronic renal disease in diabetes by decreasing the glomerular filtration rate and possibly promoting the accumulation of extracellular matrix.
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PMID:Hepatocyte growth factor: a regulator of extracellular matrix genes in mouse mesangial cells. 1071 43

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.
Diabetes 2000 Aug
PMID:Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats. 1092 41


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