Hypertension and renal injury in experimental polycystic kidney disease

of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys. Am J Physiol Renal Physiol 290: F897-F904, 2006. First published October 18, 2005 doi:10.1152/ajprenal.00332.2005.-Renal prostanoids are important regulators of normal renal function and maintenance of renal homeostasis. In diseased kidneys, renal cylooxygenase (COX) expression and prostanoid formation are altered. With the use of the Han:Sprague-Dawley-cy rat, the aim of this study was to determine the relative contribution of renal COX isoforms (protein, gene expression, and activity) on renal prostanoid production [thromboxane B 2 (TXB2, stable metabolite of TXA2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1␣ (6-keto-PGF1␣, stable metabolite of PGI 2)] in normal and diseased kidneys. In diseased kidneys, COX-1-immunoreactive protein and mRNA levels were higher and COX-2 levels were lower compared with normal kidneys. In contrast, COX activities were higher in diseased compared with normal kidneys for both COX-1 [0.05 Ϯ 0.02 vs. 0.45 Ϯ 0.11 ng prostanoids ⅐ min Ϫ1 ⅐ mg protein Ϫ1 (P Ͻ 0.001)] and COX-2 [0.64 Ϯ 0.10 vs. 2.32 Ϯ 0.22 ng prostanoids ⅐ min Ϫ1 ⅐ mg protein Ϫ1 (P Ͻ 0.001)]. As the relative difference in activity was greater for COX-1, the ratio of COX-1/COX-2 was higher in diseased compared with normal kidneys, although the predominant activity was still due to the COX-2 isoform in both genotypes. Endogenous and steady-state in vitro levels of prostanoids were ϳ2-10 times higher in diseased compared with normal kidneys. The differences between normal and diseased kidney prostanoids were in the order of TXB 2 Ͼ 6-keto-PGF 1␣ Ͼ PGE2, as determined by higher renal prostanoid levels and COX activity ratios of TXB 2/6-keto-PGF1␣, TXB2/PGE2, and 6-keto-PGF 1␣/PGE2. This specificity in both the COX isoform type and for the prostanoids produced has implications for normal and diseased kidneys in treatments involving selective inhibition of COX isoforms. thromboxane; prostaglandin CYCLOOXYGENASE (COX

Section: Methodsmentioning

confidence: 88%

Selectivity of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cyrat kidneys

Warford-Woolgar¹,

Peng²,

Shuhyta³

et al. 2006

“…The administration of enalaprilat, an angiotensin-converting enzyme inhibitor, or losartan, an angiotensin II type 1 receptor antagonist to 3-to 4-wk-old Han:SPRDcy rats significantly reduced renal cystic disease and the rate of decline in renal function, compared with other antihypertension agents. When administered to Han:SPRD-cy rats between 3 and 40 wk of age, enalaprilat and hydralazine exerted similar protective effects on renal function, but only enalaprilat reduced proteinuria and the progression of renal cystic disease, as assessed by kidney size (63).…”

Section: Renin-angiotensin System Blockadementioning

confidence: 93%

“…44). Several studies have demonstrated that the intrarenal renin-angiotensin system is activated in Han:SPRD-cy rats and targeted therapy attenuates disease progression (62)(63)(64). The administration of enalaprilat, an angiotensin-converting enzyme inhibitor, or losartan, an angiotensin II type 1 receptor antagonist to 3-to 4-wk-old Han:SPRDcy rats significantly reduced renal cystic disease and the rate of decline in renal function, compared with other antihypertension agents.…”

Section: Renin-angiotensin System Blockadementioning

confidence: 99%

Murine models of polycystic kidney disease: molecular and therapeutic insights

Guay‐Woodford

2003

176

160

Guay-Woodford, Lisa M. Murine models of polycystic kidney disease: molecular and therapeutic insights. Am J Physiol Renal Physiol 285: F1034-F1049, 2003 10.1152/ajprenal. 00195.2003.-Numerous murine (mouse and rat) models of polycystic kidney disease (PKD) have been described in which the mutant phenotype results from a spontaneous mutation or engineering via chemical mutagenesis, transgenic technologies, or gene-specific targeting in mouse orthologs of human PKD genes. These murine phenotypes closely resemble human PKD, with common abnormalities observed in tubular epithelia, the interstitial compartment, and the extracellular matrix of cystic kidneys. In both human and murine PKD, genetic background appears to modulate the renal cystic phenotype. In murine models, these putative modifying effects have been dissected into discrete factors called quantitative trait loci and genetically mapped. Several lines of experimental evidence support the hypothesis that PKD genes and their modifiers may define pathways involved in cystogenesis and PKD progression. Among the various pathway abnormalities described in murine PKD, recent provocative data indicate that structural and/or functional defects in the primary apical cilia of tubular epithelia may play a key role in PKD pathogenesis. This review describes the most widely studied murine models; highlights the data regarding specific gene defects and genetic modifiers; summarizes the data from these models that have advanced our understanding of PKD pathogenesis; and examines the effect of various therapeutic interventions in murine PKD.autosomal dominant polycystic kidney disease; autosomal recessive polycystic kidney disease; polycystic kidney disease quantitative trait loci; polycystic kidney disease therapeutics RENAL TUBULAR CYSTS DEVELOP in several inherited human disorders. Among these, the polycystic kidney diseases (PKD) are one of the leading causes of endstage renal disease in children and adults (31). Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1:1,000 individuals, primarily as the result of mutations in one of two genes, PKD1 or PKD2 (81,(150)(151)(152). In comparison, autosomal recessive polycystic kidney disease (ARPKD) is much less frequent (1: 20,000 live births) and results primarily from mutations in a single gene, PKHD1 (107, 162).The principal pathological manifestations in PKD involve 1) the formation of epithelial-lined cysts throughout the nephron in ADPKD and predominantly in the collecting duct in ARPKD; 2) alterations in cell polarity; and 3) changes in extracellular matrix composition. In addition to the renal cystic disease, ADPKD is associated with cyst formation in other epithelial organs, most notably the liver and pancreas, as well as connective tissue defects, such as intracranial aneurysms, aortic dissection, cardiac valve abnormalities, and abdominal wall hernias (116). In comparison, the ARPKD phenotype is expressed almost exclusively in the kidney and liver, with the latter lesion involving biliary dysgenesis a...

“…Enalapril was obtained from Sigma (St. Louis, MO). The dose of enalapril used has a significant antihypertensive effect in rats 3-12 wk of age (15,18). At the end of the 8 wk of age, rats were anesthetized by an intraperitoneal injection of pentobarbital sodium (50 mg/kg body wt) and subjected to blood pressure and RBF studies before the kidneys were removed and weighed.…”

Section: Animalsmentioning

confidence: 99%

Effect of statin and angiotensin-converting enzyme inhibition on structural and hemodynamic alterations in autosomal dominant polycystic kidney disease model

Zafar¹,

Tao²,

Falk³

et al. 2007

Zafar I, Tao Y, Falk S, McFann K, Schrier RW, Edelstein CL. Effect of statin and angiotensin-converting enzyme inhibition on structural and hemodynamic alterations in autosomal dominant polycystic kidney disease model. Am J Physiol Renal Physiol 293: F854-F859, 2007. First published June 20, 2007; doi:10.1152/ajprenal.00059.2007.-Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease and is the fourth most common cause of end-stage kidney disease. Preclinical studies to identify effective interventions to prevent or slow progression of PKD nephropathy are therefore direly needed. Heterozygous Han:SPRD rats are an autosomal dominant PKD model with many of the characteristics of AD-PKD in humans. In the present study, parameters known to antedate the decrease in renal function, namely, renal structure, renal blood flow (RBF), and mean arterial pressure (MAP), were evaluated with three different interventions, namely, HMG-CoA reductase inhibition with lovastatin, angiotensin-converting enzyme (ACE) inhibition with enalapril, and a combination of these two treatments. The statin therapy demonstrated structural and functional benefits, including increased RBF and decreased BUN, independently of a change in MAP, while the ACE inhibition therapy demonstrated structural benefit in association with a decrease in MAP. An enhancement of these protective interventions in this autosomal dominant PKD model was not demonstrated with the combined treatment.renal blood flow; renal structure; blood pressure A DECREASE IN RENAL BLOOD flow (RBF) by magnetic resonance imaging recently has been shown in patients with ADPKD to parallel the increase in total kidney volume and to precede the decline in glomerular filtration rate (GFR) (27). In a doubleblind crossover study in 10 normocholesterolemic ADPKD patients, treatment for 4 wk with 40 mg simvastatin vs. placebo demonstrated an increase in RBF and GFR (30). Other HMGCoA reductase inhibitors (i.e., statins) have been shown in animal models to ameliorate progression of nephropathy and to increase RBF (1, 12). The statin, cerivastatin, decreased blood pressure, serum creatinine, and albuminuria in rats transgenic for human renin and angiotensin with hypertension, cardiac hypertrophy, renal damage, and marked albuminuria (20).There is considerable evidence that the renin-angiotensin system (RAS) is activated in ADPKD patients. The plasma renin and aldosterone responses to posture and angiotensinconverting enzyme (ACE) inhibition were greater in ADPKD patients than patients with essential hypertension of comparable age, gender, blood pressure, renal function, and urinary sodium excretion (3). Angiotensinogen, ACE, angiotensin II type I (AT 1 ) receptor, and angiotensin II have been found within cysts and tubules of ADPKD kidneys, thus implicating intrarenal RAS (19). Immunoreactive renin also has been found in tubules and cyst fluid of ADPKD kidneys (26).The effect of statin therapy with lovastatin to diminish the severity of renal d...