Renal Hypertrophy In Experimental Diabetes Research Articles

The growing importance of mTORC1-S6K1 signaling in kidney

renal hypertrophy, which aptly describes the condition of increased kidney mass attributable to enlargement more so than proliferation of tubular and glomerular cells, can occur under many circumstances, but the underlying mechanism(s) remain poorly understood. Diabetes mellitus is a common disease

Mycophenolate mofetil (RS 61443): nothing new under the sun or an important break-through in the field of transplantation?

of glucose concentration on angiotensin 11-induced hypertrophy of proximal tubular cells in culture. Biochem Biophys Res Commun 1991; 176: 902-909 14. Flyvbjerg A, Bornfeldt KE, Marshall SM, Arnqvist HJ, Orskov H. Kidney IGF-I mRNA in initial renal hypertrophy in experimental diabetes in rats. Diabetologia 1990; 33: 334-338 15. Wolf G, Sharma K, Chen Y, Ericksen M, Ziyadeh FN. High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-0. Kidney Int 1992; 42: 647-656 16. Crowley ST, Brownlee M, Edelstein D et al. Effects of nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells. Diabetes 1991; 40: 540-547 17. Nakamura T, Fukui M, Ebihara I et al. mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 1993; 42: 450-456 18. Ayo SH, Radnik RA, Glass WF et al. Increased extracellular matrix synthesis and mRNA in mesangial cells grown in highglucose medium. Am J Physiol 1991; 260: F185-F191 19. Ziyadeh FN, Sharma K, Ericksen M, Wolf G. Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-/?. J Clin Invest 1994; 93: 536-542 Nephrol Dial Transplant 1995: Editorial Comments

Increased ornithine decarboxylase activity in kidneys undergoing hypertrophy in experimental diabetes

Renal hypertrophy and hyperfiltration are early manifestations of human and experimental diabetes that may contribute to the late development of diabetic nephropathy. The biochemical events resulting in kidney growth in the diabetic state are completely unknown. Since growth of various tissues is accompanied by increased formation of polyamines, we studied whether polyamines were involved in the growth of the kidney observed in diabetic rats. This was done by measuring the activity of the rate-limiting enzyme in the polyamine pathway (ornithine decarboxylase; ODC) in kidneys from control, diabetic and insulin-treated diabetic animals. The ODC activity in the kidney was increased in the diabetic animals with a maximal rise 24 h after diabetes induction (6-fold, P< 0.01); the activity thereafter declined. However, on day 14 the activity was still significantly elevated (2.5-fold, P< 0.05). In insulin-treated diabetic animals the kidney ODC activity was only increased 3-fold ( P< 0.05) after 24 h, and for the rest of the study period the activity was about 1.8-fold higher than in control rats. After 14 days the kidneys from diabetic rats were significantly larger than kidneys from both control and insulin-treated diabetic rats, 1066 ± 43 mg vs. 904 ± 16 mg and 959 ± 36 mg, respectively ( P< 0.01). For comparison, the ODC activity was also investigated in muscle. However, in muscle from diabetic animals the ODC activity declined steadily during the 14 days to 34% of control values ( P< 0.01), and insulin treatment completely normalized the ODC activity in muscle. Our findings demonstrate for the first time an early increase in kidney ODC activity preceding renal hypertrophy in experimental diabetes. Furthermore, insulin treatment of diabetic rats reduced the diabetes-induced increase in ODC activity and prevented the kidney growth associated with diabetes. These findings support the idea that polyamines may be involved in diabetic renal hypertrophy.

Octreotide administration in diabetic rats: Effects on renal hypertrophy and urinary albumin excretion

Initial renal hypertrophy in experimental diabetes is prevented by administration of a long-acting somatostatin analogue octreotide (SMS). To investigate the long-term effects of SMS on renal hypertrophy and urinary albumin excretion (UAE), streptozotocin-diabetic and non-diabetic rats were treated with two daily subcutaneous injections of SMS (100 micrograms x 2) for six months. Untreated diabetic and non-diabetic animals were used as reference groups. No differences were seen between the two diabetic groups in respect to body weight, food intake, blood glucose levels, urinary glucose output, hemoglobin A1C(HbA1C), fructosamine, serum growth hormone (rGH) or creatinine clearance, but kidney weight (896 +/- 36 vs. 1000 +/- 24 mg, P less than 0.02), UAE (417 +/- 131 vs. 1098 +/- 187 micrograms/24 hr, P less than 0.02), kidney insulin-like growth factor I (IGF-I) (167 +/- 16 vs. 239 +/- 17 ng/g, P less than 0.01) and serum IGF-I (301 +/- 26 vs. 407 +/- 17 micrograms/liter, P less than 0.01) were all reduced in the SMS-treated diabetic animals when compared to the untreated diabetic group. In non-diabetic rats SMS reduced body weight (274 +/- 3 vs. 293 +/- 5 g, P less than 0.01), kidney weight (695 +/- 9 vs. 764 +/- 17 mg, P less than 0.01), UAE (83 +/- 29 vs. 364 +/- 114 micrograms/24 hr, P less than 0.02), kidney IGF-I (202 +/- 12 vs. 280 +/- 12 ng/g, P less than 0.01), serum IGF-I (428 +/- 21 vs. 601 +/- 54 micrograms/liter, P less than 0.01) and serum rGH (67 +/- 6 vs. 126 +/- 27 micrograms/liter, P less than 0.05) when compared to untreated controls. When kidney weights were expressed in relation to body weight no difference was found between SMS-treated and untreated controls, while the difference between SMS-treated and untreated diabetic animals was still present (P less than 0.01). In conclusion, chronic administration of SMS has abating effects on diabetic renal hypertrophy and UAE, and thus indicates that SMS may reduce development of diabetic kidney lesions in experimental diabetes. The long-term suppressive effects of SMS on renal enlargement and UAE may in part be mediated through reduction in circulating and kidney IGF-I levels.

Renal hypertrophy in experimental diabetes

Renal hypertrophy in experimental diabetes

Dietary fish oil enhances renal hypertrophy in experimental diabetes

Renal hypertrophy occurs early in the natural history of human and experimental diabetes and may be a manifestation of the same pathophysiological process which ultimately results in diabetic nephropathy. The precise biological events which stimulate and regulate this growth process remain incompletely understood. We postulated that renal eicosanoids contribute to the development of renal hypertrophy in diabetes. We elected to test the effects of suppression of dienoic eicosanoid metabolism (arachidonic acid metabolism) on renal hypertrophy in diabetic rats by feeding fish oil. Diabetic rats fed fish oil had markedly reduced insulin requirements compared to control rats pair-fed a beef tallow-rich diet. The concentrations of prostaglandin E 2, 6-keto-prostaglandin F 1α, and thromboxane B 2 were depressed in the renal cortex of diabetic rats fed fish oil. This alteration in eicosanoid metabolism was associated with a substantial enhancement of diabetic renal hypertrophy. These results indicate that dietary fish oil has profound effects on renal eicosanoid metabolism in experimental diabetes and that these autocoids may participate in the biological events which regulate diabetic renal hypertrophy.

Additive Increase in Kidney Insulin-Like Growth Factor I and Initial Renal Enlargement in Uninephrectomized-Diabetic Rats

The initial renal hypertrophy in experimental diabetes and in response to uninephrectomy is associated with renal accumulation of insulin-like growth factor I (IGF-I). Since the combination of diabetes and nephrectomy almost doubles the initial renal growth rate the aim of the present study was to investigate the kidney IGF-I levels in the combined situation in uninephrectomized diabetic rats. Three experimental groups were exposed to either unilateral nephrectomy, streptozotocin-diabetes or both conditions and for four days animals from each group were taken out for investigation. After 4 days the wet kidney weight increased from baseline by 31% (from 661 +/- 16 mg (SEM) to 866 +/- 27 mg) (P less than 0.01) in the uninephrectomized group, 32% (to 872 +/- 18 mg) (P less than 0.01) in the diabetic group and 46% (to 962 +/- 27 mg) (P less than 0.01) in the uninephrectomized-diabetic group. Kidney IGF-I concentrations were analyzed by radioimmunoassay and the increase from baseline on day 2 was 74% (from 262 +/- 12 ng/g (SEM) to 456 +/- 21 ng/g) (P less than 0.01) in the uninephrectomized group, 58% (to 414 +/- 18 ng/g) (P less than 0.01) in the diabetic group and 176 +/- % (to 722 +/- 56 ng/g) (P less than 0.01) in the combined group. Thereafter a decline in kidney IGF-I occurred in all groups, being normal at day 4 for the diabetic group, but still significantly higher in the uninephrectomized and uninephrectomized-diabetic groups compared to controls (P less than 0.05%).(ABSTRACT TRUNCATED AT 250 WORDS)

Kidney IGF-I mRNA in initial renal hypertrophy in experimental diabetes in rats

It has recently been demonstrated that immunoassayable kidney insulin-like growth factor I concentration increases 24-48 h after induction of diabetes, preceding the initial renal hypertrophy. To elucidate whether this increase is due to increased local production we studied rat kidney insulin-like growth factor I gene expression during the first four days after induction of streptozotocin diabetes. Eighteen hours after injection with streptozotocin the diabetic animals were divided into two groups, one of which was treated with insulin, and daily for four days animals from each group were taken out for investigation. After four days the wet kidney weight had increased from baseline by 20% (from 687 +/- 23 to 827 +/- 6 mg (mean +/- SEM), p less than 0.01) in the untreated diabetic group, while no significant increase occurred in the insulin-treated group (687 +/- 23 vs 732 +/- 21 mg, NS). Kidney insulin-like growth factor I increased rapidly from baseline, the rise amounting to 52% after 48 h (from 271 +/- 11 to 411 +/- 32 ng/g, p less than 0.01) with a decline to control level on day four in the untreated diabetic group. Kidney insulin-like growth factor I remained unchanged in the insulin-treated diabetic group. Insulin-like growth factor I mRNA was measured by solution-hybridization assay. No differences were found in kidney insulin-like growth factor I mRNA between the two diabetic groups over the study period, while in liver, insulin-like growth factor I mRNA tended to be lower on day four in diabetic rats when compared to insulin-treated rats (p = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Kidney tissue insulin-like growth factor I and initial renal growth in diabetic rats: Relation to severity of diabetes

The initial renal hypertrophy in experimental diabetes is dependent on the prevailing blood glucose level and is associated with renal accumulation of insulin-like growth factor I. To investigate the relationship of blood glucose to kidney IGF-I, a graded range of diabetic aberration was established in young rats by iv injection of increasing amounts of streptozotocin (25-80 mg/kg) at day 0. In 30 diabetic rats the mean of day 1 and day 2 blood glucose concentrations ranged from 6.2 to 32.0 mmol/l and 24-h urinary glucose excretion (24-48 h) from 0.04 to 43.3 mmol/24 h. The right kidneys were removed after 48 h, weighed and their IGF-I concentration analysed by radioimmunoassay. Kidney IGF-I was positively correlated to blood glucose (r = 0.66, p less than 0.0001) as well as to 24-h urinary glucose output (r = 0.54, p less than 0.005). At this early stage, kidney weight already correlated to blood glucose (r = 0.60, p less than 0.0005). No relationship between kidney IGF-I and kidney weight was found. However, if animals with severe diabetes were excluded, a significant correlation could be established (r = 0.51, p = 0.01, N = 24). The results support the hypothesis that IGF-I plays a causal role in the initial renal hypertrophy of experimental diabetes.

Renal hypertrophy in experimental diabetes. The activity of the ‘de novo’ and salvage pathways of protein synthesis

Renal hypertrophy in experimental diabetes. The activity of the <i>‘de novo’</i> and salvage pathways of protein synthesis

Renal hypertrophy in experimental diabetes. The activity of the ‘de novo’ and salvage pathways of purine [corrected] synthesis

Measurements were made of the activity of phosphoribosyl pyrophosphate amidotransferase (PPRibP-At, EC 2.4.2.14) and of adenine (APRT, EC 2.4.2.7) and hypoxanthine (HPRT, EC 2.4.2.8) phosphoribosyltransferases, representing the 'de novo' and salvage pathways respectively. PPRibP-At activity increased within 3 days of diabetes, whereas APRT and HPRT increased later. Incorporation of [14C]formate and of [8-14C]adenine into the nucleic acids of kidney slices showed that formate was incorporated earlier, and to a greater extent, than was adenine. These results indicate that, although the 'de novo' pathway for nucleotide synthesis is the main route in early diabetes, the salvage pathway assumes greater importance at later stages.

Stimulation of Phosphatidylcholine Biosynthesis in Diabetic Hypertrophic Kidneys*

Choline metabolism and phosphatidylcholine biosynthesis were studied in renocortical slices of rats rendered diabetic with streptozotocin. The rates of [14C]choline incorporation into both acid-soluble and acid-insoluble fractions were increased in diabetic relative to control kidneys. While choline uptake into the control kidneys reached a plateau after 30 min of incubation, the tissue uptake of choline by the diabetic kidneys showed a time-dependent increase over 120 min, rising to a level exceeding that of control kidneys. In the control kidney, the oxidation of choline to betaine was similar to the level of phosphocholine accumulation during the first 30 min, while the formation of phosphocholine in the diabetic kidney was 1.9-fold higher than that in the control kidney (P less than 0.02) and 1.4-fold higher than the formation of betaine in diabetics (P less than 0.05). These data suggest that most of the choline transported into cells enters the Kennedy pathway by phosphorylation to phosphocholine in diabetic kidneys. The diabetic kidney also demonstrated a marked increase in the formation of three choline-containing phospholipids; phosphatidylcholine, lysophosphatidylcholine, and sphingomyelin. The treatment of diabetes with insulin restored these abnormalities toward normal. The absolute content of phosphatidylcholine significantly increased in diabetic kidneys (P less than 0.05) while contents of other major phospholipids and total lipid phosphorus in diabetic kidneys were not different from those in control kidneys. Our results indicate that renal hypertrophy in experimental diabetes is associated with a stimulation of the biosynthesis of renal phosphatidylcholine, presumably caused by an enhanced tissue uptake of choline and a stimulation of choline kinase. Since an enhancement of the membrane phosphatidylcholine biosynthesis is one of the early responses to growth signals, an alteration in phosphatidylcholine biosynthesis may contribute to the development of renal hypertrophy in experimental diabetes.

Renal hypertrophy in experimental diabetes: Some functional aspects

Glomerular filtration rate (GFR) was measured by constant infusion of iothalamate in conscious rats with and without streptozotocin diabetes. Kidney weight had already increased significantly after 4 days of diabetes. GFR was unchanged at that time, but increased subsequently, so that GFR/kidney weight was normal after 1 month of diabetes. Tubular glucose reabsorption rate was increased to the same extent as kidney weight after 4 days of diabetes. It is concluded that renal growth in experimental diabetes cannot be initiated by glomerular hyperfiltration, but that increased glucose reabsorption may have a causal role.

Renal hypertrophy in experimental diabetes. Effect of diabetes on the pathways of glucose metabolism: differential response in adult and immature rats.

The effect of short-term diabetes, 5 days after the administration of streptozotocin, on renal growth and the activity of alternative pathways of glucose metabolism was studied in immature (21-day-old) rats and in adult rats. The kidney weight increased by 28% in the adult diabetic rats, but by only 10% in the immature diabetic rats, relative to their age-matched control groups. The flux of glucose via the pentose phosphate pathway was increased 2-3-fold in the adult diabetic rats, but was unchanged in the immature diabetic group. Enzymes of this pathway (glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase) increased by 29% and 77% respectively in adult diabetic rats; in the immature group they showed changes of +5% and +28% respectively. The rate of glucose phosphorylation increased significantly in both groups of diabetic rats; only minor changes were observed in oxidation via the tricarboxylic acid cycle. Increases of 40-50% were found in the activity of enzymes involved in UDP-glucose metabolism (phosphoglucomutase, UDPglucose pyrophosphorylase and UDPglucose dehydrogenase) and in lactate dehydrogenase in both young and adult animals. The results suggest a differential renal response to streptozotocin-diabetes according to the stage of renal growth and development, and it is proposed that the difference is related to the developmental emergence of aldose reductase. Enzymes involved in formation of ribose 5-phosphate and NADPH are strikingly increased in the adult diabetic, whereas metabolic functions dependent on a high ambient glucose concentration, e.g. synthesis of glycogen and glucuronate, are similarly affected in adult and immature diabetic groups, both showing certain aspects of 'glucose overutilization'.

Renal hypertrophy in experimental diabetes. Changes in pentose phosphate pathway activity.

An examination was made of the effect of different periods of experimental diabetes on the activity of the pentose phosphate pathway in rat kidney. A rapid increase in kidney weight, expressed both in absolute terms and in terms of body weight, occurred shortly after the induction of diabetes. The activity of the enzymes of the oxidative segment of the pentose phosphate pathway and the flux of glucose through the pathway were both increased during the first 7 days after induction of diabetes. Thereafter, enzyme activity returned toward control levels, but the increased functional activity of the pathway, as measured using specifically labeled glucose, persisted. In contrast, transketolase was significantly depressed at the time of most rapid kidney growth. A positive correlation was found between the rate of kidney growth and the change in activity of glucose-6-phosphate dehydrogenase and a negative correlation with changes in transketolase activity. The possible roles of the oxidative and nonoxidative segments of the pentose phosphate pathway in the kidney in early diabetes-induced renal hypertrophy are discussed.

Renal hypertrophy in experimental diabetes. Changes in pentose phosphate pathway activity

Renal hypertrophy in experimental diabetes. Changes in pentose phosphate pathway activity

Acute renal hypertrophy in experimental diabetes: lack of effect of short-term growth hormone administration.

Normal and diabetic rats were given daily injections of human growth hormone for four days (5 mg per rat per day). Injected rats showed no differences from uninjected controls with respect to kidney weight or renal content of protein, RNA or DNA. Kidney weight increased by 7% after two days of diabetes and by 20% after four days, but growth hormone caused no augmentation of the hypertrophy. It is concluded that growth hormone plays no role in the initiation of diabetic renal hypertrophy.

Renal hypertrophy in experimental diabetes. A morphometric study.

Renal hypertrophy in rats with streptozotocin diabetes or after unilateal nephrectomy was studied by sterological techniques. -- After 4 days of diabetes total glomerular volume had increased by 30%, and after 47 days by 43%. Glomerular growth was more pronounced than whole kidney growth during the first 4 days, but subsequently whole kidney growth exceeded glomerular growth. In control rats glomerular volume was 4.9% of total kidney volume; after 4 days of diabetes it was 5.4% and after 47 days 4.1%. -- Proximal tubule length increased from 366 m/kidney in control rats to 447 m/kidney after 47 days of diabetes; tubular luminal diameter increased from 26.8 micrometer to 31.4 micrometer in the same rats. Tubular length and luminal diameter were, however, not increased after 4 days of diabetes. -- In unilaterally nephrectomised rats there was no early rapid glomerular growth. Glomerular fractional volume was 4.9% in controls, 4.4% at four days, and 4.2% at 24 days after nephrectomy. -- The results indicate a disturbed glomerulo-tubular balance in the early phases of diabetic renal hypertrophy.

Renal hypertrophy in experimental diabetes: relation to severity of diabetes.

Streptozotocin diabetic rats have larger kidneys than non-diabetic rats. In the present study the rate of kidney growth during the first seven days of diabetes was correlated with the blood glucose concentration. Over a wide range of blood glucose concentrations (116-340 mg/100 ml) the kidney weight, protein content and protein/DNA ratio were closely correlated with the glucose values.