The Streptozotocin (STZ) model of diabetes is commonly used for studies of diabetic nephropathy although the histological lesions of the kidney are mild and do not resemble those seen in diabetic patients. The SHR/N-cp rat model of type II diabetes spontaneously develops pronounced abnormalities in renal histology. In the present study, we compared renal morphology in the STZ rat and the diabetic SHR/N-cp rat. Sprague-Dawley rats received STZ, developed diabetes after 2 days and were treated with insulin. In the SHR/N-cp rat, obesity is inherited as an autosomal recessive trait. The progeny are either lean (used as controls) or obese and diabetic. After 6 months of observation, STZ and SHR/N-cp rats were killed. The renal damage was evaluated by assessing damage indices and by using stereological techniques. In addition, immunohistochemistry and electron microscopy were performed. The glomerular and tubulointerstitial changes were much more pronounced in the diabetic SHR/N-cp compared to the STZ model. In parallel glomerular PCNA þ cells were significantly more frequent and expression of TGF-b and PDGF by immunohistochemistry in glomeruli and in the tubulointerstitial space was more pronounced in SHR/N-cp compared to STZ rats. The glomeruli of SHR/Ncp contained less and larger podocytes as well as smaller mesangial cells embedded in more mesangial matrix compared to STZ. Similarly, less, but larger endothelial cells were found in SHR/N-cp than in STZ rats. The mean glomerular volume was similarly increased in the two models. Albumin excretion was only modestly increased in STZ diabetes, but pronounced in the SHR/N-cp rat. Although the STZ model of diabetes exhibits numerous biochemical sequelae of hyperglycemia, the morphological lesions are unimpressive. In contrast, the diabetic SHR/N-cp exhibits marked structural lesions, particularly podocyte damage and mesangial expansion that promise to make it a more suitable model for investigation of diabetic glomerulosclerosis.

Aims/hypothesis. It was the aim of our study to investigate the influence of a selective ET-A receptor antagonist LU 135252 alone and in combination with the ACE-inhibitor, trandolapril on podocyte number and morphology in streptozotocin diabetic rats. Methods. Male Sprague-Dawley rats were injected with 65 mg streptozotocin i.v. and subsequently developed diabetes. Animals were left untreated or received daily either trandolapril (0.3 mg/kg body weight), LU 135252 (50 mg/kg body weight) or a combination of both. After 6 months the experiment was terminated. Glomerular geometry and cellularity were assessed by stereological techniques. Protein expression of TGF-β, ET-1, PDGF-AB, fibronectin, desmin and α-smooth muscle cell actin was investigated by immunohistochemistry.Results. The mean number of podocytes per glomerulus was lower (86±17 vs. 138±25; p<0.05) and mean podocyte volume was higher in untreated diabetic animals than in non-diabetic controls. Only ACE-i alone and in combination, but not ET A -RB alone prevented loss of podocytes and podocyte hypertrophy. In diabetic rats, increased numbers of PCNA positive and p27 kip1 positive cells (mainly podocytes) were reduced by all treatments, but only ACE-i decreased numbers of desmin positive podocytes and tubulointerstitial expression of TGF-β. Albuminuria was increased in untreated diabetes and was prevented only by ACE-i and combination treatment. Conclusion/interpretation. Podocyte hypertrophy and degeneration is an early event in diabetic nephropathy leading to a loss of podocytes. Treatment with an ACE-i, but not with an ET A -RB, prevented the development of albuminuria as well as damage and loss of podocytes. The well known anti-proteinuric effect of ACE-i is presumably due at least in part to conservation of podocyte structure. Increased plasma endothelin-1 (ET-1) concentrations and urine excretion of ET-1 have been documented in patients with diabetes and proteinuria [1]. It has been shown that experimental diabetes mellitus increases renal ET-1 gene transcription [2]. To assess the relevance of the ET-system in the pathogenesis of renal structural changes in the model of the STZ-induced diabetic rat we compared the effect of an ET A -receptor specific antagonist with the well known beneficial effect of an ACE-i, especially on podocyte cell number and morphology. [Diabetologia (2003) 46:856-868]

Erythrocyte sodium-potassium (Na+/K+)-ATPase and sodium-lithium (Na+/Li+) countertransport activities were measured in 18 children (aged 9.6 years, range 6-16 years) with idiopathic hypercalciuria (IHU) to evaluate cellular Na handling. The effect of chronic thiazide administration on these parameters and on bone mineral density was also evaluated. Patients with IHU had significantly lower erythrocyte Na+/K+-ATPase activity than 23 age-matched healthy controls (mean +/- SEM 2,156 +/- 110 micromol P/l erythrocyte per hour vs. 3,165 +/- 175, P < 0.01). Thiazide treatment significantly lowered urinary calcium excretion; this was followed by a slight suppression of intact parathyroid hormone (iPTH). The urinary calcium/creatinine ratio before and during treatment was 0.90 +/- 0.07 mmol/mmol versus 0.51 +/- 0.06 respectively, P < 0.01. The corresponding iPTH levels were 5.9 +/- 0.6 pmol/l and 5.1 +/- 0.7, P < 0.05. The Na+/K+-ATPase activity increased significantly (2,769 +/- 169 micromol P/l erythrocyte per hour vs. 2,156 +/- 110 in the control period, P < 0.01) and the Na+/Li+ countertransport decreased (268 +/- 28 micromol Li/l erythrocyte per hour vs. 328+26 in the control period, P < 0.03). The bone mineral density Z score rose from -1.3 +/- 0.26 to -0.8 +/- 0.22 (P < 0.03). We conclude that IHU is accompanied by abnormalities of erythrocyte Na+/K+-ATPase and Na+/Li+ countertransport which are corrected by chronic hydrochlorothiazide administration. These changes could model alterations in renal tubular transport mechanisms still to be elucidated. Chronic thiazide treatment also has a positive effect on bone mineral density.

Gastric proton pump inhibitors are widely used in the treatment of dyspeptic problems and for the eradication of H. pylori infection. Data are not available on whether omeprazole, a representative of proton pump inhibitors, influences the function of osteoclastic H+-pump in children. We studied the impact of short-term omeprazole administration on the biochemical parameters of bone turnover in pediatric patients. Urinary calcium excretion, serum total alkaline phosphatase activity, collagen type 1 crosslinked C-telopeptide, and osteocalcin levels were determined in 34 children [20 girls (9 prepubertal) and 14 boys (6 prepubertal)] before and after 2 weeks of omeprazole treatment at a dose of 20 mg/day. The measured parameters were within the healthy reference range in each patient. None of them altered during the study in any age or in any gender. We conclude that omeprazole, at a dose of 20 mg/day, does not significantly influence the investigated biochemical parameters of osteoclast and osteoblast function in pediatric patients.

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