Empagliflozin increases kidney weight due to increased cell size in the proximal tubule S3 segment and the collecting duct.

The inhibition of renal SGLT2 glucose reabsorption has proven its therapeutic efficacy in chronic kidney disease. SGLT2 inhibitors (SGLTi) have been intensively studied in rodent models to identify the mechanisms of SGLT2i-mediated nephroprotection. So far, the overwhelming effects from clinical trials, could only partially be reproduced in rodent models of renal injury. However, a commonly disregarded observation from these studies, is the increase in kidney weight after SGLT2i administration. Increased kidney mass often relies on tubular growth in response to reabsorption overload during glomerular hyperfiltration. Since SGLT2i suppress hyperfiltration but concomitantly increase renal weight, it seems likely that SGLT2i have a growth promoting effect on the kidney itself, independent of GFR control. This study aimed to investigate the effect of SGLT2i on kidney growth in wildtype animals, to identify enlarged nephron segments and classify the size increase as hypertrophic/hyperplastic growth or cell swelling. SGLT2i empagliflozin increased kidney weight in wildtype mice by 13% compared to controls, while bodyweight and other organs were not affected. The enlarged nephron segments were identified as SGLT2-negative distal segments of proximal tubules and as collecting ducts by histological quantification of tubular cell area. In both segments protein/DNA ratio, a marker for hypertrophic growth, was increased by 6% and 12% respectively, while tubular nuclei number (hyperplasia) was unchanged by empagliflozin. SGLT2-inhibition in early proximal tubules induces a shift of NaCl resorption along the nephron causing compensatory NaCl and H2O reabsorption and presumably cell growth in downstream segments. Consistently, in collecting ducts of empagliflozin-treated mice, mRNA expression of the Na+-channel ENaC and the H2O-channels Aqp-2/Aqp-3 were increased. In addition, the hypoxia marker Hif1α was found increased in intercalated cells of the collecting duct together with evidence for increased proton secretion, as indicated by upregulation of carbonic anhydrases and acidified urine pH in empagliflozin-treated animals. In summary, these data show that SGLT2i induce cell enlargement by hypertrophic growth and possibly cell swelling in healthy kidneys, probably as a result of compensatory glucose, NaCl and H2O hyperreabsorption of SGLT2-negative segments. Particularly affected are the SGLT2-negative proximal tubules (S3) and the collecting duct, areas of low O2 availability.

A Preliminary Study of Organ Weight After Histological Exclusion of Abnormality During Autopsy in the Adult Population of Uttarakhand, India.

Organomegaly can be a strong predictor of an underlying pathological condition. There are many standard tables available in various texts listing the normal organ weight range, yet there is a lack of a standard table that is accepted globally. The main reason behind this is variation in organ weight due to socioeconomic status, geographical variation, and racial and stature variation among different global populations. The Western population has different stature compared to our population, that is, residents of Uttarakhand, India. Different studies tabulated organ weights in different regions of the world and correlated with different bodily parameters such as sex, race, stature, BMI, etc, which have shown a significant variation. There are different sets of data available that cannot be accepted universally due to regional variation. Most of the studies done in various parts of the world do not specify the condition of the organ, whether it was normal at the time of study or not. The methods of dissection of organs were also not explained in different studies. In this study, a total of eight organs were weighed from 137 autopsies conducted at the mortuary of the All India Institute of Medical Sciences Rishikesh over a period of 1.5 years. It was found that the average brain weighed in males was 1313.2 gm (±127.7 gm) and among females, it was 1218.0 gm (±122.82 gm). The weight of the heart was 310.1 gm (±83.97 gm) in males and 241.2 gm (±71.42 gm) in females. Right and left lungs weighed 499.4 gm (±207.5 gm)/407.5 gm (±128.66 gm) and 459.6 gm (±179.19 gm)/369.4 gm (±144.17 gm) among males and females, respectively. The liver weight was 1477.0 gm (±370.52 gm) in males and 1309.0 gm (±274.18 gm) among females. Spleen weighed 154.0 gm (±74.63 gm) in males and 156.0 gm (±65.0 gm) in females. The right and left kidneys weighed 125.9 gm (±37.92 gm)/108.1 gm (±28.80 gm) and 126.3 gm (±31.26 gm)/106.6 gm (±22.4 gm) among males and females, respectively. In our study, we have done a histological examination to rule out any pathological condition before including the weight of the organs in the study. The present study is to derive a standard organ weight among the inhabitants of Uttarakhand, India, and to look for a variation in organ weight among different studies done in the past in different regions of the world.

Methyl cellosolve-induced renal oxidative stress and time-dependent up-regulation of pro-inflammatory cytokines, apoptotic, and oncogenic markers in rats.

Methyl cellosolve (MC) is used in production of textile, paints, stains, inks, surface coatings, and anti-icing additive in hydraulic fluids and jet fuel. Consequently, the present study investigated its effect on renal cells, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of MC for a period of 7, 14, and 21 days. Following 7 days of administration of MC, there was a significant increase in the levels of K-Ras, c-Myc, TNF-α, IL-6 and NO, while GSH level and SOD activity were significantly reduced compared with control. At the end of 14 days exposure, RKW, GSH, NO, and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1ß, IL-6, MDA and GPx activity were significantly increased compared with control. After 21 days of MC administration, RKW, GSH, NO, IL-10 and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1ß, IL-6, MDA and GST activity were significantly increased compared with control. Exposures to MC in any way should be strictly avoided as it could trigger renal damage through the disorganization of the antioxidant system, up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

Nephrotoxicity and highly active antiretroviral therapy: Mitigating action of Momordica charantia.

Momordica charantia (M. charantia) is known for its antioxidant and antidiabetic properties. The aim of this study is to investigate the renoprotective effects of M. charantia in rats following treatment with highly active antiretroviral therapy (HAART) regimen triplavar. Adult male Sprague-Dawley rats weighing 178.1-220.5 g (n = 36) were divided into six groups (A-F) with each group comprising of six (n = 6) rats. The drugs and extract were administered via oral gavage. The therapeutic dose of triplavar was adjusted using the human therapeutic dose equivalent for the rat model. Animals were euthanized on the tenth week with kidneys removed for examination and blood obtained via cardiac puncture. Levels of oxidative stress enzymes (superoxide dismutase-SOD, catalase-CAT, and reduced glutathione-GSH) were significantly lowered in all groups not receiving M. charantia. The levels of thiobarbituric acid reactive substances (TBARS) were increased resulting in free radical formation via auto-oxidation. Renal parameters showed no albuminuria, normal blood urea nitrogen (BUN), serum creatinine (SCr) and electrolytes in groups treated with M. charantia. HAART treated (Group B) showed severe albuminuria, a significantly (p < 0.05) raised BUN and SCr and gross electrolyte disturbances. Blood glucose levels were significantly raised in groups not receiving the adjuvant M. charantia (p < 0.05). Histopathology in HAART treated animals showed glomerular capillary abnormalities and cellular infiltrations while M. charantia treated animals showed an essentially normal glomerular appearance with capillary loops and normal cytoarchitecture. In conclusion M. charantia extract administration improved blood glucose levels, restored renal histology, reinstate renal function, reduce body weight loss and restores hyperglycemia.

Prenatal exposure to angiotensin II increases blood pressure and decreases salt sensitivity in rats.

Renin angiotensin aldosterone system (RAAS) plays an essential role in the homeostatic control of arterial blood pressure, perfusion of tissues, and control of extracellular fluid. Its components are highly expressed in the developing kidney, general vasculature, brain, and heart. A modified intrauterine environment alters mechanisms controlling blood pressure (BP) and can lead to hypertension in the adult offspring and developmentally programmed RAAS can be involved in this process. There are very little data about the effects of increased angiotensin II (Ang II) concentrations during pregnancy on in utero development of the fetus. In our study, we administered Ang II to pregnant female rats via osmotic mini-pumps and evaluated the postnatal development and BP control in the offspring. To estimate possible developmental changes in sensitivity to salt, we exposed the offspring to a diet with increased salt content and measured plasma aldosterone levels and plasma renin activity. Increased Ang II during pregnancy raised BP in the offspring; however, salt sensitivity was decreased in comparison to controls. Relative weight of the left ventricle was decreased in the offspring prenatally exposed to Ang II, while relative kidney weight was reduced only in female offspring. Prenatal treatment led to increased aldosterone levels and decreased plasma renin activity, suggesting a complex physiological response. Our results suggest that conditions leading to upregulation of RAAS during pregnancy can influence the cardiovascular system of the fetus and have a long-term impact on the offspring's health.

[Differentially expressed genes in the locus associated with relative kidney weight and resting blood pressure in hypertensive rats of the ISIAH strain].

The comparative full-genome sequencing of transcriptomes of the renal cortex and medulla from hypertensive ISIAH rats and normotensive WAG rats revealed the differential expression of genes in the locus of chromosome 11 associated to the traits of resting blood pressure and relative kidney weight. Six differentially expressed genes (Kcne1, Rcan1, Mx1, Mx2, Tmprss2, and RGD1559516) were identified in the renal cortex, and three genes (Rcan1, Mx2, and Tmprss2) were identified in the renal medulla. An analysis of the functions of these genes pointed at the Rcan1 gene as the most relevant candidate gene associated with both the traits of resting blood pressure and relative kidney weight in ISIAH rats. The elevation of the transcription levels of the Mx1 and Mx2 genes in hypertensive ISIAH rats may represent an adaptation that contributes to the alleviation of inflammatory processes in the kidneys.

DL-propargylglycine reduces blood pressure and renal injury but increases kidney weight in angiotensin-II infused rats.

Hydrogen sulfide (H2S), carbon monoxide (CO) and nitric oxide (NO) share signaling and vasorelaxant properties and are involved in proliferation and apoptosis. Inhibiting NO production or availability induces hypertension and proteinuria, which is prevented by concomitant blockade of the H2S producing enzyme cystathionine γ-lyase (CSE) by d,l-propargylglycine (PAG). We hypothesized that blocking H2S production ameliorates Angiotensin II (AngII)-induced hypertension and renal injury in a rodent model. Effects of concomitant administration of PAG or saline were therefore studied in healthy (CON) and AngII hypertensive rats. In CON rats, PAG did not affect systolic blood pressure (SBP), but slightly increased proteinuria. In AngII rats PAG reduced SBP, proteinuria and plasma creatinine (180 ± 12 vs. 211 ± 19 mmHg; 66 ± 35 vs. 346 ± 92 mg/24 h; 24 ± 6 vs. 47 ± 15 µmol/L, respectively; p < 0.01). Unexpectedly, kidney to body weight ratio was increased in all groups by PAG (p < 0.05). Renal injury induced by AngII was reduced by PAG (p < 0.001). HO-1 gene expression was increased by PAG alone (p < 0.05). PAG increased inner cortical tubular cell proliferation after 1 week and decreased outer cortical tubular nucleus number/field after 4 weeks. In vitro proximal tubular cell size increased after exposure to PAG. In summary, blocking H2S production with PAG reduced SBP and renal injury in AngII infused rats. Independent of the cardiovascular and renal effects, PAG increased HO-1 gene expression and kidney weight. PAG alone increased tubular cell size and proliferation in-vivo and in-vitro. Our results are indicative of a complex interplay of gasotransmitter signaling/action of mutually compensatory nature in the kidney.

The relationship between chemical-induced kidney weight increases and kidney histopathology in rats.

The kidney is a major site of chemical excretion, which results in its propensity to exhibit chemically-induced toxicological effects at a higher rate than most other organs. Although the kidneys are often weighed in animal toxicity studies, the manner in which these kidney weight measurements are interpreted and the value of this information in predicting renal damage remains controversial. In this study we sought to determine whether a relationship exists between chemically-induced kidney weight changes and renal histopathological alterations. We also examined the relative utility of absolute and relative (kidney-to-body weight ratio) kidney weight in the prediction of renal toxicity. For this, data extracted from oral chemical exposure studies in rats performed by the National Toxicology Program were qualitatively and quantitatively evaluated. Our analysis showed a statistically significant correlation between absolute, but not relative, kidney weight and renal histopathology in chemically-treated rats. This positive correlation between absolute kidney weight and histopathology was observed even with compounds that statistically decreased terminal body weight. Also, changes in absolute kidney weight, which occurred at subchronic exposures, were able to predict the presence or absence of kidney histopathology at both subchronic and chronic exposures. Furthermore, most increases in absolute kidney weight reaching statistical significance (irrespective of the magnitude of change) were found to be relevant for the prediction of histopathological changes. Hence, our findings demonstrate that the evaluation of absolute kidney weight is a useful method for identifying potential renal toxicants.

A study to evaluate the effect of ratio of donor kidney weight to recipient body weight on renal graft function.

AIM AND OBJECTIVES: To study the effect of the ratio of donor kidney weight (dkw) to recipient body weight (rbw) on short and long term graft function in live donor kidney transplant patients. MATERIALS AND METHODS: It was a prospective study of 79 live donor kidney transplant recipients. Patients were divided into three groups depending on the ratio of dkw in grams to rbw in kilograms. Serum creatinine in milligrams percent on the day of surgery, 7(th) day, 1 month, 6 months, 1 year, and 3 years after the surgery was recorded and their means compared. RESULTS: The comparison showed that the decrease in mean creatinine level was more in group three patients as compared with group 2 and one patients at 7 days (1.04,1.44 and 1.59 in group 3,2 and 1 respectively) and 30 days (1.12,1.36 and 1.45 in group 3,2 and 1 respectively), showing that higher dkw/rbw ratio is beneficial with respect to the early graft function. However this decrease was not statistically significant (P value -0.256 and 0.358 respectively on 7(th) and 30(th) day). Furthermore long-term function was not different among these three groups. CONCLUSION: The ratio of dkw to rbw does not have a significant effect on long-term graft function inspite of an early improvement in the function with increased dkw to rbw ratio.

Low-dose of multi-glycoside of Tripterygium wilfordii Hook. f., a natural regulator of TGF-ß1/Smad signaling activity improves adriamycin-induced glomerulosclerosis in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Transforming growth factor (TGF)-ß1/Smad signaling pathway plays a critical role in the prolonged glomerulosclerosis (GS), which is an important determinant during the progression in chronic kidney disease (CKD). For recent 30 years, multi-glycoside of Tripterygium wilfordii Hook. f. (GTW), an extract from Chinese herbal medicine has been proved clinically effective in improving GS in CKD in China. However, therapeutic mechanisms involved in vivo are still unclear. In this study, we aimed to explain the dose-effects and molecular mechanisms of GTW on GS by regulating TGF-ß1/Smad signaling activity in adriamycin (ADR)-induced nephropathy (ADRN). MATERIALS AND METHODS: Rats with ADRN, created by unilateral nephrectomy and twice adriamycin injections (ADR, 4 mg/kg and 2 mg/kg) within 4 weeks, were divided into four groups, the Sham group, the Vehicle group, the low-dose GTW-treated group, and the high-dose GTW-treated group, and that, sacrificed at the end of the 6th week after administration. Proteinuria, blood biochemical parameters, glomerulosclerotic morphological makers, podocyte shape, and nephrin expression were examined, respectively. Protein expressions of key signaling molecules in TGF-ß1/Smad pathway, such as TGF-ß1, Smad3, phosphorylated-Smad2/3 (p-Smad2/3), and Smad7, were also evaluated individually. RESULTS: The results indicated that the characterizations of ADRN involved the typical prolonged GS, a small amount of abnormal proteinuria, and the failing renal function; TGF-ß1/Smad signaling molecules, especially Smad3, p-Smad2/3, and Smad7 were activated in vivo, accompanied by the exasperation of glomerulosclerotic lesion; GTW at high-dose (100 mg/kg) and low-dose (50 mg/kg) could slightly ameliorate the prolonged GS and nephrin expression, furthermore, the anti-proliferative action of GTW at high-dose was superior to that at low-dose, but caused the significant liver injury; in ADRN model rats, protein expressions of TGF-ß1, p-Smad2/3, and Smad7 in the kidneys could be regulated with the treatment of GTW at low-dose. CONCLUSION: This study farther demonstrated that the low-dose of GTW, as a natural regulator in vivo, could effectively and safely ameliorate the prolonged GS in FSGS model, via the potential molecular mechanisms involving the reduction of ECM components and the suppression of TGF-ß1 over-expression, as well as the bidirectional regulation of TGF-ß1/Smad signaling activity.

A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats.

BACKGROUND: Cisplatin (cis-diamminedichloroplatinum II; CP) is used widely as an antitumor drug in clinics, but is accompanied with renal toxicity. Cisplatin induced nephrotoxicity consists of change in kidney weight, histological changes in kidney and increase in serum creatinine (Cr) and blood urea nitrogen (BUN). This study was designed to find out a model for prediction of cisplatin induced nephrotoxicity. MATERIALS AND METHODS: Pathological damage score, kidney weight, BUN, and Cr of 227 rats that were involved in different projects were determined. A total of 187 rats were treated with 7 mg/kg cisplatin and sacrificed 1 week later. RESULTS: There was a good significant correlation between normalized kidney weight and logarithmic scale of BUN and Cr. Relationship between BUN, Cr or normalized kidney weight and pathology damage score was significant. CONCLUSION: Normalized kidney weight and pathology damage score is a good predictor of renal function in cisplatin induced nephrotoxicity in experimental rats.

Superior renoprotective effects of the combination of breviscapine with enalapril and its mechanism in diabetic rats.

Breviscapine is a flavonoid extracted from a Chinese herb Erigeron breviscapus, previously it was shown that treatment with breviscapine attenuated renal injury in the diabetic rats. The purpose of this study was to investigate whether breviscapine combined with enalapril (an ACE inhibitor) have superior renoprotective effects against diabetic nephropathy. Rats were randomly separated into five groups: control, diabetes, diabetes treated with enalapril, diabetes treated with breviscapine, or diabetes treated with combined enalapril with breviscapine. Twenty-four hours urinary AER and the levels of 3-NT in renal tissue and MDA in renal tissue and urine as well as activities and expression of PKC in renal tissue were determined, and renal tissue morphology were observed by light microscopy after 8 weeks. Expression of TGFß1 protein was performed by immunohistochemistry method. Increased AER and kidney pathologic injury were attenuated by treatment with either enalapril or breviscapine and further reduced by the combination of the two. Elevated 3-NT in renal tissue and MDA levels in renal tissue and urine were reduced by enalapril or breviscapine and, more effectively, by combined enalapril with breviscapine. PKC activities and expression were higher in renal tissue in diabetic rats than those of the control group, which were reduced by both monotherapies, and further abrogated by combination therapy in both cases. Overexpression of TGFß1 protein observed in the glomeruli and tubulointerstitium of diabetic rats was attenuated by enalapril or breviscapine to a similar lever and further reduced by the combination of the two. The combination of enalapril and breviscapine confers superiority over monotherapies on renoprotection, which mechanism may be at least partly correlated with synergetic suppression on increased oxidative stress and PKC activities as well as overexpression of TGFß1 in renal tissue.

Protective effects of Cordyceps sinensis on experimental rats with diabetic kidney / 国际中医中药杂志

Objective To observe the Cordyceps extract on experimental rats with diabetic kidney and to explore its mechanism of action.Methods The rat models of diabetic were established by intraperitoneal injecting streptozotocin.Kidney weight and the index of kidney were measured,and 1,4,7weeks blood sugar,serum creatinine,urine microalbumin and urea were dynamically observed for evaluating Cordyceps extract on experimental rats with diabetic kidney.Results The 1,4,and 7 weeks of kidney weight was (0.662± 0.062) g,(0.670±0.061) g,(0.657±0.063) g,renal index was (0.312±0.041) ％,(0.309±0.402) ％,(0.311 ±0.0317) ％,serum creatinine was (0.51±0.03)mg/d1,(0.57±0.03)mg/d1,(0.52±0.02)mg/d1,albumin was (1.77±0.17)mg/24 h,(1.52±0.19)mg/24 h,(1.56±0.11)mg/24 h.urea was (90.71 ±0.37)mmol/L,(91.57±0.48) mmol/L,(90.56±0.39)mmol/L in the normal control group respectively.While in the model group,the value of kidney weight was (0.879±0.037)g,(0.912±0.038)g,(0.871±0.393)g,renal index was (0.494±0.039)％,(0.487±0.038)％,(0.465±0.235)％,serum creatinine was (3.71 ±0.14) mg/d1,(3.51±0.12) mg/d1,(3.32±0.11)mg/d1,urinary albumin was (7.29±0.22)mg/24 h,(7.11±0.34)mg/24 h,(7.14±0.21)mg/24 h.urea was (109.59± 8.42),(92.52±2.41),(90.71 ±0.67) respectively.Compared with the normal control group these values were decreased significantly in the model group (P＜0.05).In the Cordyceps sinensis group kidney weight was (0.837±0.036)g,(0.747±0.029)g,(0.694±0.357)g,renal index was (0.412±0.024)％,(0.395±0.037)％,(0.361±0.027)％,serum creatinine was (1.44±0.11)mg/d1,(0.81± 0.04) mg/d1,(0.62±0.03) mg/d1,urinaryalbumin was (5.71±0.25)mg,(4.52±0.21)mg,(3.96±0.15)mg,urea was (109.59± 8.42) mmol/L,(92.52±2.41) mmol/L,(90.71 ± 0.67) mmol/L respectively.Compared with the model group these values were decreased significantly(P＜0.05) in the Cordyceps sinensis group.Conclusion Cordyceps sinensis extract has a protective effect on kidney of diabetic rats.

Factors Affecting the First 3-year Quality of Graft Function after Live Donor Kidney Transplantation

PURPOSE: We designed this study to identify the risk factors affecting the quality of graft after live donor kidney transplantation. METHODS: The study cohort included 259 adult patients who had been followed up for an average of 37 months after transplantation. Cyclosporine (CsA) and steroids were used as main immunosuppressive agents. Seven variables [HLA match, numbers of acute rejection (AR) within post-transplant 1 year, blood type compatibility, use of anti-lymphocyte antibody, age of donor (DA), age of recipient, and the donor kidney weight to recipient body weight ratio (KW/BW)] were examined by multiple regression analysis during the first 3 years. Serum creatinine (Scr), creatinine clearance rate (Ccr) and the 24 hours urinary excretion of protein (24 UP) were used as parameters. RESULTS: AR, DA, or KW/BW independently affected the quality of graft function. Scr, Ccr, or 24 UP at post-transplant 1 year was strongly correlated with AR (p<0.0001, p=0.002, or p=0.002, respectively). However, Scr, Ccr, or 24 UP at post-transplant 3 years was strongly affected by KW/BW (p<0.0001, p<0.0001, or p=0.008, respectively) or DA (p<0.0001, p=0.001, or p=0.039, respectively). CONCLUSION: Non-immunologic factors independently affected the graft function through the study periods. The impact of non-immunologic factors on the function of the graft increased year by year. During renal allocation, KW/BW and DA should be included as reference indices to improve the long-term graft function.

Effect of long-term administration of somatostatin analogue on renal enlargement in uninephrectomized-diabetic rats

Recent study has demonstrated that the long-acting somatostatin analogue administration effectively prevented initial renal growth in diabetic and uninephrectomized rats. In the present study we examined long-term effect of somatostatin analogue (Sandostatin) on renal enlargement in uninephrectomized-diabetic rat5. Animals were divided into 4 groups: (1) normal control rats (C) (n = 7), (2) uninephrectomized rats (NPX) (n = 7), (3) uninephrectomized-diabetic rats (NPX + DM) (n = 7) and (4) NPX + DM rats treated with Sandostatin (NPX + DM + Tx) (n = 9). All animals had free access to diet (50% protein) and water during the experimental period. To the NPX + DM + Tx rats, 2.5 micrograms of Sandostatin was given subcutaneously twice a day for 8 weeks. Periodic observations were done at 0, 4 and 8 weeks. After 8 weeks. NPX rats (0.540 +/- 0.017 (SEM)) had higher fractional kidney weights (FKW) (wet kidney wt/body wt) compared to C rats (0.410 +/- 0.014) (p < 0.0005), and both NPX + DM rats (0.983 +/- 0.098) and NPX + DM + Tx rats (1.091 +/- 0.042) had higher FKW compared to C rats (p < 0.0001) and NPX rats (p < 0.005), respectively. But no significant change of FKW was observed between NPX + DM rats and NPX + DM + Tx rats. Systolic blood pressure, BUN, serum creatinine, glomerular filtration rate and 24 hour urine protein excretion in NPX + DM rats were not different from those in NPX + DM + Tx rats.(ABSTRACT TRUNCATED AT 250 WORDS)