Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant polycystic kidney disease is a common (approximately 1 in 400 individuals in the United States) inherited disorder, in which hypertension is the most often associated disorder. Although the development of hypertension originates with expansion of renal cysts, it most likely has its pathogenesis in the renal vasculature. Evidence is now accumulating that the renin-angiotensin-aldosterone system is important in the development and maintenance of hypertension in this disorder. End-organ damage including left ventricular hypertrophy and progressive renal insufficiency appear to be related to the presence of hypertension in ADPKD. A focus on early detection and adequate control of hypertension in ADPKD, therefore, may be associated with improved cardiovascular and renal outcomes as well as increased patient survival in ADPKD.
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PMID:Pathogenesis of hypertension in autosomal dominant polycystic kidney disease. 176 38

The Han: SPRD Pkd rat mutant is an autosomal dominant rat model with incomplete penetration of polycystic renal transformation. Progressive renal failure occurs in heterozygous male animals. The mechanisms of progression have not been elucidated. To identify some pathogenetic factors involved we subjected male SPRD Pkd rats (and their non-affected littermates as controls) to uninephrectomy (UNX), castration or enalapril treatment. To assess progression S-urea at age 150 days was chosen as endpoint. (i) In uninephrectomized male Han: SPRD Pkd (n = 12 animals per group) S-urea at age 150 days was consistently above 300 mg/dl, while it was 245 mg/dl (191-290) in control Han: SPRD Pkd. (ii) In castrated male Han: SPRD median S urea at 150 days was 100 mg/dl (69-211) compared to sham-operated male Han: SPRD controls (245; 191-290). Castration did not, however, prevent accelerated progression after uninephrectomy. (iii) Enalapril (50 mg/l) in the drinking fluid did not significantly lower median systolic blood pressure (by plethysmography) in animals on 0.2% sodium diet (at 185 days 160 mmHg; 140-170 versus 170; 140-195 in non-enalapril controls), although circulating ACE was significantly inhibited (17 U; 11-33 versus 89; 52-108 in controls). S-urea at age 185 days was not significantly different in the 2 groups. In conclusion, the Han: SPRD Pkd model differs from human ADPKD to some extent. Uninephrectomy accelerates renal failure in the rat, but not in humans. On the other hand, in contrast to human ADPKD the renin system is suppressed in the rat model and ACE inhibition does not affect the course of renal failure.
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PMID:Progression of renal failure in the Han: SPRD polycystic kidney rat. 770 56

The Han:SPRD rat model for inherited polycystic kidney disease (PKD) was characterized (clinical parameters, morphology, immunohistochemistry and in situ hybridization). Homozygous animals died of uremia after three to four weeks with severe cystic transformation of virtually all nephrons and collecting ducts (serum urea: 616 +/- 195 mg/dl; kidney-to-body weight ratio: > 20%). In heterozygotes, slow progression of the disease led to death between the 12th and 21st month (median: 17 months; serum urea levels above 200 mg/dl). Kidney enlargement was moderate, and cysts were restricted to the cortex and outer medulla. Immunohistochemical markers showed that approximately 75% of the cysts were derived from the proximal tubule. Cystic transformation started in the proximal tubule with a sharp onset of basement membrane alteration and a loss of epithelial differentiation restricted to small focal areas. In these areas, alpha 1(IV) collagen and laminin B1 mRNA were enhanced as revealed by isotopic and non-isotopic in situ hybridization. Fibroblasts underlying the affected tubular portions were involved in matrix overexpression resulting in subepithelial accumulation of immunoreactive collagen IV and laminin. In later stages of cystic transformation distal nephron segments were affected as well. A reversal in epithelial polarity as judged from Na,K-ATPase-immunoreactivity was not observed. Renal immunoreactive renin-status was significantly decreased. Hematocrit was lowered in heterozygotes (40.4 +/- 5.8 vol% compared to 46.7 +/- 1.99 vol% in controls; P < 0.05) and total renal EPO mRNA was reduced to 36 +/- 14% of the mean value of control animals, whereas serum EPO levels were not significantly altered. We conclude that the Han:SPRD rat is a useful model for the study of human ADPKD since both diseases are similar in several aspects. The model is particularly suitable for the study of epithelial-mesenchymal interactions at the beginning of tubular cystic transformation.
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PMID:Characterization of the Han:SPRD rat model for hereditary polycystic kidney disease. 793 31

Autosomal dominant polycystic kidney disease (AD-PKD) has a variable clinical course. Clinical parameters associated with a worse prognosis are hypertension and proteinuria or microalbuminuria (MA). Because chronic stimulation of the renin-angiotensin system is likely to be present in ADPKD patients, the effect of the angiotensin-converting enzyme insertion/deletion (ACE I/D) genotype on the variability of these clinical parameters was examined in untreated ADPKD patients. Proteinuria and MA were determined in 24-h urine collections. BP measurements were performed with an ambulatory monitor, over 24 h. With analysis of covariance, the ACE genotype was found to be significantly associated with MA, corrected for age, gender, GFR, mean arterial pressure, body surface area, and urinary Na+ excretion (P < 0.05). The patients homozygous for the deletion (DD) had the highest rate of MA (P < 0.05) compared to the patients homozygous for the insertion (II). There was no relationship between the ACE genotype and BP or renal function. A significant positive correlation was found between MA and mean arterial pressure (r = 0.31, P < 0.05), whereas a significant negative correlation was found between MA and renal function (r = -0.28, P < 0.05). In conclusion, in ADPKD patients, MA is partly determined by the ACE I/D polymorphism. Because MA is associated with an enhanced progression toward renal failure, the ACE genotype could help in identifying patients at risk for a worse prognosis.
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PMID:The angiotensin-converting enzyme genotype and microalbuminuria in autosomal dominant polycystic kidney disease. 1047 43

Autosomal dominant polycystic kidney disease (ADPKD) is the result of mutations in one allele of the PKD1 or PKD2 genes, followed by "second hit" somatic mutations of the other allele in renal tubule cells. Continued proliferation of clonal cells originating from different nephron segments leads to cyst formation. In vitro studies of the mechanisms of cyst formation have been hampered by the scarcity of nephrectomy specimens and the limited life span of cyst-derived cells in primary culture. We describe the development of a series of immortalized epithelial cell lines from over 30 individual renal cysts obtained from 11 patients with ADPKD. The cells were immortalized with either wild-type (WT) or temperature-sensitive (TS) recombinant adeno-simian virus (SV)40 viruses. SV40 DNA integration into the cell genome was verified by PCR analysis. The cells have been passaged over 50 times with no apparent phenotypic change. By light microscopy, the cells appear pleomorphic but mostly polygonal and resemble the primary cultures. Transmission electron microscopy shows polarized epithelia with tight junctions. The SV40 large T antigen was detected by immunocytochemistry and by Western blot analysis at 37 degrees C in the WT cell lines and at 33 degrees C in the TS cell lines. It disappeared in TS cells 72 h following transfer to 39 degrees C. The majority (29) of the cell lines show binding of Dolichos biflorus lectin, suggesting distal tubule origin. Three cell lines show binding of Lotus tetragonolobus lectin or express aminopeptidase N, suggesting proximal tubule origin. Three cell lines were derived from a mixture of cysts and express features of both tubules. The PKD1 and PKD2 mRNA and protein were detected in all cells by RT-PCR and by immunocytochemistry. The majority of the cells tested also express the epidermal growth factor receptor, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and renin. These new series of cyst-derived cell lines represent useful and readily available in vitro models for studying the cellular and molecular biology of ADPKD.
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PMID:Immortalized epithelial cells from human autosomal dominant polycystic kidney cysts. 1273 1

Autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease, is characterized by the development of hypertension and end stage renal disease. An increase in the activity of the renin-angiotensin system, due to a renal ischemia caused by cyst expansion, contributes to the development of hypertension and renal failure in ADPKD. Recently, the angiotensinogen (AGT) gene, M235T, and angiotensin II type 1 receptor (ATR) gene, A1166C, polymorphisms have been associated with the susceptibility to develop hypertension and renal disease. We hypothesized that the AGT M235T and ATR A1166C polymorphisms could account for some of the variability in the progression of ADPKD. Genotyping was performed in 108 adult patients with ADPKD, and 105 normotensive healthy controls, using PCR and restriction digestion. We analyzed the effects of the AGT M235T and ATR A1166C polymorphisms on hypertension and age at the end stage renal disease (ESRD). Of the 108 patients with ADPKD, 64 (59%) had hypertension and 24 (22%) reached the ESRD. The prevalence of hypertension were; [MM+MT], [TT] genotypes, 60%, 59% (p=1.00); [AA], [AC+CC] genotypes, 60%, 50% respectively (p=0.54). The ages at the onset of ESRD were; [MM+MT], [TT] genotypes, 50 +/- 9 years, 56 +/- 8 years (p=0.07); [AA], [AC+CC] genotypes, 54 +/- 8 years, 52 +/- 14 years, respectively (p=0.07). There were no differences in the prevalence of hypertension and the ages at the ESRD in relation to the AGT M235T and ATR A1166C polymorphisms. We suggest that the AGT and ATR gene polymorphisms would not have an effect on hypertension or the ESRD in ADPKD.
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PMID:Angiotensinogen and angiotensin II type 1 receptor gene polymorphism in patients with autosomal dominant polycystic kidney disease: effect on hypertension and ESRD. 1295 Jan 20

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation. End-stage ADPKD renal tissue extracts and cyst fluids were assayed for time-dependent, chymostatin-inhibitable conversion of (125)I-AngI to (125)I-AngII under conditions of ACE and aminopeptidase inhibition by means of HPLC. Thirteen of 14 ADPKD kidney extracts exhibited chymase-like AngII-generating capacity; calculated initial reaction rates averaged 3.9 +/- 2.9 fmol AngII/min/ micro g protein with a mean maximal conversion of 55% +/- 30% of added substrate. AngII-generating activity was both protein and substrate dependent. All five cyst fluid samples were negative. Chymase-like activity was detectable in only three of six non-ADPKD kidney extracts. Immunoreactive chymase protein was present in/around mast cells within the fibrotic renal interstitium in all samples. Findings demonstrate for the first time the presence of mast cells, mast cell-associated immunoreactive chymase protein, and chymase-like AngII generating capacity in ADPKD cystic kidneys. Results support the potential for ACE-independent AngII generation and for mast cell-initiated inflammatory processes in ADPKD, each with therapeutic implications for ADPKD renal progression.
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PMID:Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease. 1474 98

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening, hereditary disease. The prevalence of ADPKD is more common than Huntington disease, haemophilia, sickle cell disease, cystic fibrosis, myotonic dystrophy and Down syndrome combined. In recent years there have not only been advances in the understanding of the genetic and molecular events involved in ADPKD, but some diagnostic and therapeutic advances have also emerged. In the genetics area, the gene for PKD1 was localised to chromosome 16, is associated with polycystin-2 protein, and found to account for approximately 85% of patients with ADPKD. The gene for PKD2, found in chromosome 4, accounts for approximately 15% of ADPKD, and is associated with the polycystin-2 protein. While these genetic and molecular biology findings have stimulated a great deal of exciting basic research in ADPKD, therapies to decrease morbidity and mortality in ADPKD patients have yet to emerge from these findings. In contrast, the early diagnosis and treatment of hypertension with inhibitors of the renin-angiotensin-aldosterone system have the potential to decrease or prevent left ventricular hypertrophy cardiac complications and slow the progression of the renal disease.
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PMID:Optimal care of autosomal dominant polycystic kidney disease patients. 1688 82

Polycystic kidney diseases (autosomal dominant and autosomal recessive) are progressive renal tubular cystic diseases, which are characterised by cyst expansion and loss of normal kidney structure and function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common life- threatening, hereditary disease. ADPKD is more prevalent than Huntington's disease, haemophilia, sickle cell disease, cystic fibrosis, myotonic dystrophy and Down's syndrome combined. Early diagnosis and treatment of hypertension with inhibitors of the renin-angiotensin-aldosterone system (RAAS) and its potential protective effect on left ventricular hypertrophy has been one of the major therapeutic goals to decrease cardiac complications and contribute to improved prognosis of the disease. Advances in the understanding of the genetics, molecular biology and pathophysiology of the disease are likely to facilitate the improvement of treatments for these diseases. Developments in describing the role of intracellular calcium ([Ca(2+)](i)) and its correlation with cellular signalling systems, Ras/Raf/mitogen extracellular kinase (MEK)/extracellular signal-regulated protein kinase (ERK), and interaction of these pathways with cyclic adenosine monophosphate (cAMP) levels, provide new insights on treatment strategies. Blocking the vasopressin V(2) receptor, a major adenylyl cyclase agonist, demonstrated significant improvements in inhibiting cytogenesis in animal models. Because of activation of the mammalian target of rapamycin (mTOR) pathway, the use of sirolimus (rapamycin) an mTOR inhibitor, markedly reduced cyst formation and decreased polycystic kidney size in several animal models. Caspase inhibitors have been shown to decrease cytogenesis and renal failure in rats with cystic disease. Cystic fluid secretion results in cyst enlargement and somatostatin analogues have been shown to decrease renal cyst progression in patients with ADPKD. The safety and efficacy of these classes of drugs provide potential interventions for experimental and clinical trials.
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PMID:Potential pharmacological interventions in polycystic kidney disease. 1803 88

The kidney has both afferent (sensory) and efferent (sympathetic) nerves that can influence renal function. Renal innervation has been shown to play a role in the pathogenesis of many forms of hypertension. Hypertension and flank pain are common clinical manifestations of autosomal dominant (AD) polycystic kidney disease (PKD). We hypothesize that renal innervation contributes to the hypertension and progression of cystic change in rodent PKD. In the present study, the contribution of renal innervation to hypertension and progression of renal histopathology and dysfunction was assessed in male Han:SPRD-Cy/+ rats with ADPKD. At 4 weeks of age, male offspring from crosses of heterozygotes (Cy/+) were randomized into either 1) bilateral surgical renal denervation, 2) surgical sham denervation control, or 3) nonoperated control groups. A midline laparotomy was performed to allow the renal denervation (i.e., physical stripping of the nerves and painting the artery with phenol/alcohol). Blood pressure (tail cuff method), renal function (BUN) and histology were assessed at 8 weeks of age. Bilateral renal denervation reduced the cystic kidney size, cyst volume density, systolic blood pressure, and improved renal function (BUN) as compared with nonoperated controls. Operated control cystic rats had kidney weights, cyst volume densities, systolic blood pressures, and plasma BUN levels that were intermediate between those in the denervated animals and the nonoperated controls. The denervated group had a reduced systolic blood pressure compared with the operated control animals, indicating that the renal innervations was a major contributor to the hypertension in this model of ADPKD. Renal denervation was efficacious in reducing some pathology, including hypertension, renal enlargement, and cystic pathology. However, sham operation also affected the cystic disease but to a lesser extent. We hypothesize that the amelioration of hypertension in Cy/+ rats was due to the effects of renal denervation on the renin angiotensin system.
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PMID:Contribution of renal innervation to hypertension in rat autosomal dominant polycystic kidney disease. 1848 Apr 17


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