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We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. Diabetes mellitus (DM) is one of the leading causes of death in the United States and is the most common cause of end-stage renal disease (Centers for Disease Control and Prevention, 2008). Evidence suggests that the decline in renal function associated with advancing diabetes is due to a prolonged state of nitric oxide (NO) deficiency (Huang et al., 2009).
Although not extensive, there is increasing data investigating the effect of NO on the transporters involved in urine concentration. Declining NO concentration in the diabetic kidney may exacerbate the potential for hypovolemic shock by further disturbing the urine concentration mechanism, which is already compromised by osmotic diuresis. Animal protocols were approved by the Emory University Institutional Animal Care and Use Committee.
Rats from all four experimental groups were placed in metabolic cages for 24 h before sacrifice and urine was collected under oil to prevent evaporation. Kidneys were removed and dissected into outer medulla (OM), base of the IM, and tip of the IM. Age-matched male Sprague Dawley rats from the following experimental groups were individually placed in metabolic cages to monitor physiological changes for 24 h: (1) control rats, (2) rats treated with L-NAME, (3) DM rats, and (4) DM rats treated with L-NAME (Table 1). The goal of this study was to determine how declining NO in the diabetic kidney affects the already compromised urine concentrating mechanism. Investigation of AQP2 revealed that L-NAME treatment did not affect AQP2 expression in the papilla but did lower protein levels in the IM base. Long-term treatment of rats with L-NAME can reduce medullary blood flow resulting in a major effect on sodium and water homeostasis and promoting the development of hypertension in these animals (Cowley et al., 1995).
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Renal handling of glucose provides the classic example of a Tm limited reabsorptive system. Glucose not reabsorbed in the proximal tubule will not be reabsorbed in more distal segments of the nephron. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button.
This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Advancing diabetes results in osmotic diuresis and polyuria placing the patient at risk for hypovolemic shock. In fact, the IM, which is the primary site of urine concentration, expresses all three isoforms of NOS and has the highest capacity for NO synthesis compared to other nephron segments (Wu et al., 1999).
NO stimulates a cGMP-mediated pathway that results in phosphorylation and trafficking of AQP2 to the apical plasma membrane of the inner medullary collecting duct (IMCD) where the transporter is functional (Bouley et al., 2005). Therefore, the present study was designed to investigate if the diabetes-driven compensatory action of various transporters involved in concentrated urine production is compromised in the absence of NO production.
Male Sprague Dawley rats weighing 150–200 g, were allowed free access to water and fed standard rat chow. DM animals showed elevated blood glucose at the time of sacrifice confirming hyperglycemia. Although the functional difference remains a mystery, abundance of the two glycoproteins of UT-A1 (117 and 97-kDa) differ based on tissue location. This transporter is distinguished as multiple glyco-forms ranging from 45- to 65-kDa (Blount et al., 2008) as detected in control rats (Figure 2A). L-NAME treatment did not affect AQP2 expression in the papilla but did lower protein levels in the IM base (Figures 3B,E). Rats treated with L-NAME did not have any alteration in NKCC2 protein abundance (Figure 4B).
Using STZ-induced diabetic rats, we found that L-NAME-mediated inhibition of NO alleviated the polyuria observed in untreated diabetes.
Collectively, these studies have found that DM induces an increase in both UT-A1 and UT-A3 protein abundance in an attempt to restore inner medullary interstitial urea, which is disrupted in the advancement of the disease. Our findings are in agreement; total UT-A1 expression was significantly upregulated throughout the IM of diabetic rats, particularly in the IM base. This corresponds to studies that documented decreased AQP2 expression in the IM of rats orally treated with L-NAME for 6 weeks (Albertoni Borghese et al., 2007). We did not measure blood pressure in our experimental animal groups however, it is probable that L-NAME-treated animals were hypertensive.
Although it seems plausible that urine flow rates may contribute to urea transporter and AQP2 expression, studies have found that protein levels of these transporters are not responsive to increased urine flow rate or loss of medullary hypertonicity (Marples et al., 1998). Outline the signs and symptoms that you would expect in a Diabetic patient keeping in mind the actions of Insulin. Introduction Main function of kidney is excretion of waste products (urea, uric acid, creatinine, etc). Blood Glucose Regulation Glucose is the most common respiratory substrate utilised by cells, and is the sole energy source for the brain.
Glucose reabsorption occurs only in the proximal tubule, primarily in the cells of the early proximal tubule.

Therefore, the appearance of glucose in the urine signifies that FGLUCOSE exceeds TmGLUCOSE in the proximal tubule. We examined how lack of NO affects the transporters involved in urine concentration in diabetic animals. Similar to uncontrolled DM, transgenic mice with all three NOS isoforms ablated also display polyuria (Morishita et al., 2005). NO inhibits NKCC2, hindering sodium transport in the thick ascending limb (Herrera et al., 2009). Urine urea concentration was determined using Infinity Urea Reagent from Thermo Scientific (Thermo Fisher Scientific).
SDS was added to a final concentration of 1%, and the samples were sheared with a 25-gage needle. The densitometries from each group of animals were averaged and the data were presented as means ± SE for the percent change from the control value. Shown is a representative western blot of inner medulla (IM) tip (A) and base (D) probed for UT-A1 where each lane represents one rat.
Rats treated with L-NAME did not demonstrate a change in UT-A3 glycoprotein abundance (Figures 2B,C).
L-NAME treatment alone did not alter basal levels of blood or urine glucose suggesting that L-NAME treatment of the DM kidney does not improve polyuria by altering glucose-dependent osmotic diuresis but by other mechanisms, including differential expression of the concentrating transporters UT-A1, UT-A3, and AQP2.
Our results present the novel finding that diabetic rats treated with L-NAME did not have the compensatory increase in UT-A1 or UT-A3 expression.
Despite the decrease in overall protein expression, L-NAME-treated DM animals still had an increase in the 117-kDa glycoprotein. These studies differ from ours in that the rats were subjected to L-NAME for 4–8 weeks whereas the rats in our study were treated with L-NAME for 3 weeks. Thus, L-NAME-induced hypertension and not NOS inhibition may be the explanation for the attenuated expression of the concentrated transporters in L-NAME-treated DM animals. At filtered loads below TmGLUCOSE 90 % of the filtered glucose is reabsorbed in the early proximal tubule. In the inner medulla (IM), the vasopressin-sensitive water channel aquaporin 2 (AQP2) is an important contributor to water reabsorption.
Urea transport does not appear to be affected by either cGMP or NO (Nonoguchi et al., 1988). Hyperglycemia was verified 24–48 h after injection using a Lifescan Ultra II glucometer. Homogenates were centrifuged at 8,000 g for 15 min, and the protein in the supernatant fractions was measured by a modified Lowry method (DC Protein Assay Kit; Bio-Rad).
To test for statistical significance between the multiple groups, we used an ANOVA followed by Newman–Keuls test.
L-NAME treatment alone did not change the total protein abundance of UT-A1 in either section of the IM nor did the inhibition of NO change the glycosylation state (Figure 1). Corroborating previous reports (Blount et al., 2008), UT-A3 abundance was increased in DM rats (Figure 2B). Densitometry was determined for all the 65-kDa smear (B) and 45-kDa glyco-form (C) in the IM tip.
In the IM tip of diabetic animals, L-NAME treatment had no effect on the unglycosylated AQP2 expression (Figure 3C) but did reduce the glycosylated AQP2 abundance to basal level (Figure 3B).
Densitometry was determined for the glycosylated (B) and unglycosylated forms (C) in the IM tip as well as the glycosylated (E) and unglycosylated forms (F) in the IM base.
Previous work has shown that UT-A1 protein abundance increases during osmotic diuresis whenever urinary urea decreases in order to continuously transport urea to the interstitium (Kim et al., 2005). In addition, we used a lower concentration of L-NAME during treatment compared to the other studies. Protein abundance of these transporters has been examined in other animal models of hypertension (Klein et al., 2006).
Diabetes Insipidus kidneys don't concentrate urine well Symptoms frequent urination strong thirst response Causes inadequate production. The ensuing osmotic diuresis and polyuria that occurs with advancing diabetes makes these transporters of particular interest for our studies. The decline in NOS activity in the renal medulla is not however, altered by glucose-dependent osmotic diuresis alone (Lee et al., 2005).
L-NAME-treated animals did not have a significant increase in urine volume compared to control animals however, urine osmolality was significantly decreased.
UT-A1 expression was significantly upregulated in both the IM tip and base of diabetic rats.
The experimental conditions were performed 5 times (n = 5) where there were 5 animals per experimental group in each cohort.
The experimental conditions were performed five times (n = 5) where there were five animals per experimental group in each cohort.
L-NAME treatment of DM animals lowered glycosylated AQP2 levels in the IM base compared to DM animals (Figure 3E) but did not alter unglycosylated AQP2 abundance (Figure 3F). To prevent saturation of bands, the blot was scanned at a lighter intensity to measure glycosylated AQP2 (A,D) and at a higher intensity to measure the unglycosylated AQP2 (A,D) however, images are gleaned from the same representative western blot. Although DM resulted in decreased urea as a urinary solute in this study, L-NAME treatment of DM rats increased the amount of urea in urine, possibly explaining the dampened increase of urea transporter proteins in the face of DM.

This could explain the increase in AQP2 expression in response to diabetes in that vasopressin can upregulate AQP2 protein levels at a transcriptional level (Nielsen et al., 2002). While these may be minor factors, alterations in NKCC2 levels have been shown to be time dependent in other animal models (Kim et al., 2003).
Urine osmolality, urine output, and expression of urea and water transporters and the Na-K-2Cl cotransporter were examined.
After the rat consumed the full dose of L-NAME, the regular water bottle was provided for ad libitum water for the remainder of that 24-h period.
L-NAME treatment of the DM rats prevented the compensatory increase in UT-A3 abundance (Figure 2). In our study, DM animals treated with L-NAME had no compensatory increase in AQP2 expression.
In our L-NAME-treated animals, which should mimic these hypertension models, we did not see a change in transporter expression levels.
The figure shows the change in glucose concentration along the length of the proximal tubule. Predictably, diabetic rats presented with polyuria (increased urine volume and decreased urine osmolality).
Antibodies that were derived and characterized in this laboratory include a COOH-terminal UT-A1 (detects UT-A1 exclusively), NH2-terminal UT-A1 (detects UT-A1 and UT-A3 simultaneously), AQP2, and NKCC2 were used to determine the level of respective protein abundances (Blount et al., 2008).
Interestingly, L-NAME treatment of diabetic rats significantly reduced the 45-kDa glycosylated form of UT-A3 (Figure 2C). Nitric oxide synthase inhibition by L-NAME has been shown to inhibit vasopressin release (Mornagui et al., 2010), perhaps explaining the lowered levels of AQP2 expression the treated DM animals.
Increased NKCC2 expression likely increases sodium reabsorption and, through counter-current multiplication, increases urine concentration.
Although the contribution of hypertension cannot be ruled out, because the expected decrease of UT-A1, AQP2, and NKCC2 was not observed, we assume that a majority of the L-NAME effects in our study is due to NOS inhibition and not hypertension. Although metabolic parameters of control rats were unaffected by L-NAME, treated diabetic rats produced 30% less urine and osmolality was restored.
The secondary antibody used for detection was Alexa Fluor 680-linked anti-rabbit IgG (Invitrogen). Although urine osmolality of L-NAME-treated DM animals was higher than untreated DM rats, the reported value did not reach significance. In the IM base of L-NAME-treated diabetic animals, 97-kDa UT-A1 abundance was statistically increased when compared to control rats but expression of this glycoprotein was also significantly decreased compared to diabetic rats (Figure 1E). Although not proven to be the mature glycosylation form of UT-A3, we found that uncontrolled diabetes increased the upper 65-kDa glycosylated form while the lower, 45-kDa form remained unchanged. Rats treated with L-NAME had no change in urine urea however DM rats had a significantly lower urine urea corresponding with the osmolality decrease.
Hyperglycemia has been linked to increased glycosylation of a variety of proteins (Martin et al., 2006). Given the likelihood that treatments of L-NAME longer than 3 weeks increases NKCC2 expression, it would be interesting to see if longer treatment periods amplifies the DM-induced compensatory upregulation of the transporter. While L-NAME treatment alone did not alter UT-A1 or UT-A3 abundance, absence of NO prevented the upregulation of both transporters in diabetic rats. It is possible that uncontrolled diabetes increases UT-A1 and UT-A3 membrane trafficking by changing the glycosylation state, which facilitates lipid raft targeting; however, we did not examine altered cellular location in our studies. NO stimulates production of cGMP which has been shown to decrease surface NKCC2 levels thus rendering the transporter inactive (Ares et al., 2008). Similarly, AQP2 and NKCC2 abundance was increased in diabetic animals however, expression of these transporters were unchanged by L-NAME treatment of diabetes. While this change was not significant from DM values, the amount of urine urea was not different than control rats. Although hyperglycemia-induced glycosylation may account for the increased presence of the 117-kDa form of UT-A1 and 65-kDa form of UT-A3 independent of nitric oxide, it does not explain the dampened total protein abundance. It is possible that the L-NAME used in our studies prevents the synthesis of cGMP allowing NKCC2 to accumulate at the plasma membrane where it is active in the DM animals contributing to the reduction of polyuria in the L-NAME-treated DM rats. Increased expression of the concentrating transporters observed in diabetic rats provides a compensatory mechanism to decrease solute loss despite persistent glycosuria. Further studies addressing the function of the urea transporter glycosylation states and lipid rafts in diabetes will need to be pursued to completely elucidate this question. Our studies found that although diabetic-induced glycosylation remained increased, total protein expression was decreased to control levels in diabetic rats treated with L-NAME. NOx levels were lowered 68% in rats treated with L-NAME when compared to control animals, confirming that L-NAME was inhibiting the production of nitric oxide. While the role of NO in urine concentration remains unclear, lowered NO associated with diabetes may be deleterious to the transporters’ response to the subsequent osmotic diuresis. This is not surprising given that NO concentration is lower in kidneys of STZ-injected diabetic rats (Palm et al., 2005).
L-NAME treatment of DM rats reduced the already lowered levels of NOx in the urine slightly.

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