Excretion of Proteins by Rat Kidney during Various Types of Diuresis

Kutina, A. V.; Zakharov, V. V.; IuV, Natochin

doi:10.1007/s10517-009-0366-9

Cited by 6 publications

(5 citation statements)

References 8 publications

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“…Variable increases in blood urea nitrogen and several urine renal biomarkers (cystatin C, Neutrophil gelatinase-associated lipocalin [NGAL], clusterin, albumin, and Kidney Injury Molecule-1 [KIM-1]) in either one or both genders were also noted primarily at doses ≥300 mg/kg/day (in mice) starting at week 1. Several urinary proteins, predominantly originating from glomerular filtrate, have previously been shown to increase with diuresis and are attributed to increased urinary output (Lina et al 1996; Kutina, Zakharov and Natochin 2008). The osmotic diuresis and associated increase in urinary albumin seen in the present study are consistent with the previously described urinary protein increases.…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of Renal Injury and Gene Expression Changes in the Male CD-1 Mouse Associated with Exposure to Empagliflozin

et al. 2018

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An increased incidence of renal tubular adenomas and carcinomas was identified in the 2-year CD-1 mouse carcinogenicity study with empagliflozin (sodium-glucose transporter 2 inhibitor) in high dose (1,000 mg/kg/day) male mice. A 13-week mouse renal investigative pathogenesis study was conducted with empagliflozin to evaluate dose dependency and temporal onset of nonneoplastic degenerative/regenerative renal tubular and molecular (genes, pathways) changes which precede neoplasia. Male and female CD-1 mice were given daily oral doses of 0, 100, 300, or 1,000 mg/kg/day (corresponding carcinogenicity study dose levels) for 1, 2, 4, 8, or 13 weeks. The maximum expected pharmacology with secondary osmotic diuresis was observed by week 1 at ≥100 mg/kg/day in both genders. Histopathologic kidney changes were first detected after 4 weeks of dosing in the male 1,000 mg/kg/day dose group, with progressive increases in the incidence and/or number of findings in this dose group so that they were more readily detected during weeks 8 and 13. Changes detected starting on week 4 consisted of minimal single-cell necrosis and minimal increases in mitotic figures. These changes persisted at an increased incidence at weeks 8 and 13 and were accompanied by minimal to mild tubular epithelial karyomegaly, minimal proximal convoluted tubular epithelial cell hyperplasia, and a corresponding increase in Ki-67-positive nuclei in epithelial cells of the proximal convoluted tubules. There were no corresponding changes in serum chemistry or urinalysis parameters indicative of any physiologically meaningful effect on renal function and thus these findings were not considered to be adverse. Similar changes were not identified in lower-dose groups in males nor were they present in females of any dose group. RNA-sequencing analysis revealed male mouse-specific changes in kidney over 13 weeks of dosing at 1,000 mg/kg/day. Treatment-related changes included genes and pathways related to p53-regulated cell cycle and proliferation, transforming growth factor β, oxidative stress, and renal injury and the number of genes with significant expression change dramatically increased at week 13. These treatment-related changes in genes and pathways were predominant in high-dose males and complemented the observed temporal renal tubular changes. Overall, these mouse investigative study results support the role of early empagliflozin-related degenerative/regenerative changes only observed in high-dose male CD-1 mice as a key contributing feature to a nongenotoxic mode of renal tumor pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Pathogenesis of Renal Injury and Gene Expression Changes in the Male CD-1 Mouse Associated with Exposure to Empagliflozin

et al. 2018

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“…Mild proteinuria associated with the diuretic effect of dapagliflozin was observed in rats for exposures 85-fold greater than the human exposures at the maximum recommended dose. Administration of diuretics in rats has previously been associated with increased urinary protein70 and N-acetyl-β-D-glucosaminidase excretion71 in the absence of renal toxicity. Proteinuria was not observed in dogs except at very high exposures of greater than 3200-fold.…”

Section: Side Effects Associated With Urinary Glucose Excretionmentioning

confidence: 99%

Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus

Whaley¹,

Tirmenstein²,

Reilly³

et al. 2012

DMSO

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Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of glucuretic, antihyperglycemic drugs that target the process of renal glucose reabsorption and induce glucuresis independently of insulin secretion or action. In patients with type 2 diabetes mellitus, SGLT2 inhibitors have been found to consistently reduce measures of hyperglycemia, including hemoglobin A1c, fasting plasma glucose, and postprandial glucose, throughout the continuum of disease. By inducing the renal excretion of glucose and its associated calories, SGLT2 inhibitors reduce weight and have the potential to be disease modifying by addressing the caloric excess that is believed to be one of the root causes of type 2 diabetes mellitus. Additional benefits, including the possibility for combination with insulin-dependent antihyperglycemic drugs, a low potential for hypoglycemia, and the ability to reduce blood pressure, were anticipated from the novel mechanism of action and have been demonstrated in clinical studies. Mechanism-related risks include an increased incidence of urinary tract and genital infections and the possibility of over-diuresis in volume-sensitive patients. Taken together, the results of Phase III clinical studies generally point to a positive benefit-risk ratio across the continuum of diabetes patients. To date, data on dapagliflozin, a selective SGLT2 inhibitor in development, demonstrate that the kidney is an efficacious and safe target for therapy, and that SGLT2 inhibition may have benefits for patients with type 2 diabetes mellitus beyond glycemic control.

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“…It was interesting to study changes in proteinuria under conditions of polyuria, associated, according to our previous fi ndings, with enhanced protein excretion [2]. Increased proteinuria and albuminuria observed after treatment with nitroarginine derivatives (1d-AVT; Table 1) were probably related to the increase in intraglomerular pressure.…”

Section: Resultsmentioning

confidence: 84%

“…Glomerular fi lter is a natural barrier preventing protein penetration into the nephron lumen; fi ltered proteins are then reabsorbed in the proximal segment of the nephron [10]. Normally, proteins are practically absent in human and animal urine [10]; however, our recent studies demonstrated transient proteinuria in healthy rats in different variants of diuresis stimulation [2] and the mechanism of this phenomenon is unknown. This physiological proteinuria can be determined by increased penetration of proteins through the glomerular fi lter.…”

mentioning

confidence: 99%

Effect of a Blocker of Nitric Oxide Production on Albumin Excretion by Rat Kidney

Kutina

IuV

2011

Bull Exp Biol Med

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Experiments on Wistar rats showed that single intraperitoneal injection nonselective NO-synthase inhibitor L-NAME in a dose of 50 mg/kg was followed by transient proteinuria and albuminuria. This effect was not reproduced by injection of ODQ, an inhibitor of intracellular effects of NO, and arginine, but D-NAME, an optical isomer of L-NAME not blocking NO-synthase, produced similar, though less pronounced effect. The degree of proteinuria and albuminuria increased in combined treatment with nitroarginine methyl esters and 1-deamino-arginine vasotocin or arginine vasopressin. Proteinuria during treatment with arginine derivatives attests to not only their effect on the charge of the filtration membrane, but also the participation of NO-dependent processes in the regulation of ultrafiltration in renal glomeruli.

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Excretion of Proteins by Rat Kidney during Various Types of Diuresis

Cited by 6 publications

References 8 publications

Pathogenesis of Renal Injury and Gene Expression Changes in the Male CD-1 Mouse Associated with Exposure to Empagliflozin

Pathogenesis of Renal Injury and Gene Expression Changes in the Male CD-1 Mouse Associated with Exposure to Empagliflozin

Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus

Effect of a Blocker of Nitric Oxide Production on Albumin Excretion by Rat Kidney

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