CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?

OBJECTIVE: In chronic pancreatitis (CP), alterations in several genes have so far been described, but only small cohorts have been extensively investigated for all predisposing genes. DESIGN: 660 patients with idiopathic or hereditary CP and up to 1758 controls were enrolled. PRSS1, SPINK1 and CTRC were analysed by DNA sequencing, and cystic fibrosis transmembrane conductance regulator (CFTR) by melting curve analysis. RESULTS: Frequencies of CFTR variants p.R75Q, p.I148T, 5T-allele and p.E528E were comparable in patients and controls. We identified 103 CFTR variants, which represents a 2.7-fold risk increase (p<0.0001). Severe cystic fibrosis (CF)-causing variants increased the risk of developing CP 2.9-fold, and mild CF-causing variants 4.5-fold (p<0.0001 for both). Combined CF-causing variants increased CP risk 3.4-fold (p<0.0001), while non-CF-causing variants displayed a 1.5-fold over-representation in patients (p=0.14). CFTR compound heterozygous status with variant classes CF-causing severe and mild represented an OR of 16.1 (p<0.0001). Notably, only 9/660 (1.4%) patients were compound heterozygotes in this category. Trans-heterozygosity increased CP risk, with an OR of 38.7, with 43/660 (6.5%) patients and 3/1667 (0.2%) controls being trans-heterozygous (p<0.0001). CONCLUSIONS: Accumulation of CFTR variants in CP is less pronounced than reported previously, with ORs between 2.7 and 4.5. Only CF-causing variants reached statistical significance. Compound and trans-heterozygosity is an overt risk factor for the development of CP, but the number of CFTR compound heterozygotes in particular is rather low. In summary, the study demonstrates the complexity of genetic interactions in CP and a minor influence of CFTR alterations in CP development.

Serum levels of adipocyte fatty acid-binding protein are decreased in chronic pancreatitis.

OBJECTIVE: Chronic pancreatitis (CP) is associated with an increased risk for diabetes mellitus and vascular disease. Adipocyte fatty acid-binding protein (AFABP) is a novel adipokine that is independently associated with the metabolic syndrome and cardiovascular disease. In the current study, we investigated serum AFABP levels in CP patients compared with sex- and body mass index-matched controls. METHODS: Adipocyte fatty acid-binding protein was determined with enzyme-linked immunosorbent assay in control subjects (n = 60) and diabetic as well as nondiabetic CP (n = 60) patients and correlated to clinical and biochemical measures of glucose and lipid metabolism, as well as renal function in both groups. RESULTS: Median serum AFABP levels were significantly lower in CP patients compared with controls (12.5 vs 20.9 µg/L, P = 0.003). Furthermore, body mass index, sex, and CP independently predicted circulating AFABP. In contrast, no significant difference in circulating AFABP could be demonstrated between diabetic and nondiabetic CP patients. CONCLUSIONS: Circulating AFABP is paradoxically lower in CP patients and does not depend on pancreatic diabetes. Our data do not support a role of circulating AFABP in metabolic and vascular risk in CP patients.

[Georg Forster's outline of a "science of man"]. / Georg Forsters Entwurf einer "Wissenschaft vom Menschen"

The major focus of the article is on Georg Forster's mode of elaborating a "science of man" in its theoretical and cultural contexts. The study aims at identifying Forster's distinct interest in the specificity of mankind and his interpretation of both the reasons for its diversity and its different stages of development. Forster, the articles argues, used a historicized version of Enlightenment natural history in order to analyse man a s a natural as well as a cultural being. At the same time, put anachronistically, Forster constituted the reciprocity of physical and cultural anthropology. However, he differs from Enlightenment historical thinking in that he interprets history as a contingency. Finally, the article maintains that Forster deliberately conceived of the "science of man" as a multidisciplinary empirical science.

[Jejunocolic fistulae after pylorus-preserving pancreatic head resection: an uncommon cause of chronic diarrhea]. / Jejunokolische Fisteln nach pyloruserhaltender Pankreaskopfresektion: eine ungewöhnliche Ursache für chronische Diarrhö

BACKGROUND: In patients with a history of pancreatic surgery, chronic diarrhea is mainly caused by exocrine pancreatic insufficiency. The authors report, for the first time, a case of jejunocolic fistulae as a cause of diarrhea and weight loss after pancreatic head resection. CASE REPORT: A 55-year-old patient presented with chronic diarrhea and cachexia. He had undergone pylorus-preserving pancreatic head resection for chronic pancreatitis 8 years earlier. A recent colonoscopy showed an uncommon anatomy of the colon. Gastroscopy and computed tomography revealed several jejunocolic fistulae as the cause of chronic diarrhea. The patient underwent surgery and the fistula-carrying parts of jejunum and colon were resected. After surgery, his clinical status improved and he gained weight. CONCLUSION: Interenteric fistulae after pylorus-preserving pancreatic head resection have not been reported so far. Impaired synchronization of gastric emptying and bile secretion could be a possible cause of autodigestion in the anastomosis region.

The hole in the stomach.

A 57 year old woman was presented to the emergency department with upper abdominal pain and left sided chest discomfort. No cardiac or pulmonary cause could be determined and the patient underwent upper gastrointestinal endoscopy. Inversion of the scope to the fundus and subsequent fluoroscopy revealed a diaphragmatic hernia with a large herniation of the gastric fundus. Immediate laparotomy showed a 3 cm orifice of the diaphragm. The orifice was widened and a partial necrosis of the incarcerated fundus was resected. The patient recovered fully and was discharged 12 days after laparotomy.

Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis.

Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.

Clusterin is protective in pancreatitis through anti-apoptotic and anti-inflammatory properties.

Clusterin is overexpressed in pancreas during the acute phase of pancreatitis. We intended to clarify the role of clusterin expression in stressed exocrine pancreas. We performed in vitro experiments in transfected AR4-2J cells with modified expression levels of clusterin and in vivo studies in clusterin-deficient mice. AR4-2J cells were exposed to agents mimicking cell-stress during pancreatitis (cerulein, hydrogen peroxide, staurosporine or lysophosphatidylcholine). Clusterin-overexpressing AR4-2J cells showed higher viability after cell stress and accordingly reduced rates of apoptosis and lessened caspase-3 activation. Blockage of endogenous clusterin expression reduced viability and enhanced apoptosis. Presence of clusterin reduced NF-kappaB activation and expression of the NF-kappaB target genes TNF-alpha and MOB-1 under cell stress. Clusterin-deficient mice showed a more severe course of acute experimental pancreatitis with enhanced rates of apoptosis and inflammatory cell infiltration. We concluded that clusterin was protective during inflammation of exocrine pancreas because of its anti-apoptotic and anti-inflammatory functions.

Hereditary chronic pancreatitis.

Hereditary chronic pancreatitis (HCP) is a very rare form of early onset chronic pancreatitis. With the exception of the young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. As well, diagnostic criteria and treatment of HCP resemble that of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, most patients have a mild disease. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2), the serine protease inhibitor, Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) have been found to be associated with chronic pancreatitis (idiopathic and hereditary) as well. Genetic testing should only be performed in carefully selected patients by direct DNA sequencing and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. Pancreatic cancer risk is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.

Characterisation of a transgenic mouse expressing R122H human cationic trypsinogen.

BACKGROUND: The R122H mutation of the cationic trypsinogen was found in patients with hereditary pancreatitis. A transgenic animal carrying this mutation could be useful as a genetic model system of pancreatitis. METHODS: Mice transgenic for the human R122H cationic trypsinogen were generated using the -205 fragment of the rat elastase promoter. The presence of the transgene was assayed in the DNA, in pancreatic mRNA and in zymogen granule lysates. Serum levels of amylase, lipase and cytokines (MCP-1, IL-6) were monitored and the histological appearance of the tissue was investigated. Pancreatitis was induced by 7 hourly injections of 50 mug/kg cerulein. The procedure was repeated twice weekly for 10 consecutive weeks. The animals were sacrificed 24 (n = 8) and 48 hours (n = 8) after the first injection and at the end of the whole treatment (n = 7). RESULTS: The transgene was detected at the genomic level and in pancreatic mRNA. The corresponding protein was found in low amounts in zymogen granule lysates. R122H mice showed elevated pancreatic lipase, but there was no spontaneous development of pancreatitis within 18 months. After induction of pancreatitis, levels of lipase (after 24 hours) and amylase (after 48 hours) were higher in R122H mice compared to controls. Repeated treatment with cerulein resulted in a slightly more severe pancreatitis in R122H animals. Amylase, lipase, and the cytokine levels were similar to controls. CONCLUSION: The R122H transgenic mouse failed to develop a spontaneous pancreatitis but a repeatedly provoked cerulein-induced pancreatitis led to a slightly more severe pancreatitis. The rather small difference in comparison to controls could be due to the low expression of the transgene in the mouse pancreas.

Expression of mutated cationic trypsinogen reduces cellular viability in AR4-2J cells.

Mutations in the human cationic trypsinogen are associated with hereditary pancreatitis. The cDNA coding for human cationic trypsinogen was subcloned into the expression vector pcDNA3. The mutations R122H, N29I, A16V, D22G, and K23R were introduced by site directed mutagenesis. We constructed an expression vector coding for active trypsin by subcloning the cDNA of trypsin lacking the coding region for the trypsin activating peptide behind an appropriate signal peptide. Expression of protein was verified by Western blot and measurement of enzymatic activity. AR4-2J cells were transiently transfected with the different expression vectors and cell viability and intracellular caspase-3 activity were quantified. In contrast to wild-type trypsinogen, expression of active trypsin and mutated trypsinogens reduced cell viability of AR4-2J cells. Expression of trypsin and R122H trypsinogen induced caspase-3 activity. Acinar cells might react to intracellular trypsin activity by triggering apoptosis.

Transforming growth factor-beta-1 variants are not associated with chronic nonalcoholic pancreatitis.

BACKGROUND: Pancreatic fibrosis is a key pathological feature of chronic pancreatitis. In vivo and in vitro data have demonstrated that pancreatic stellate cells (PSC) play a central role in pancreatic fibrosis. PSC activation and collagen synthesis are highly controlled by transforming growth factor-beta-1 (TGF-beta1). We evaluated whether functionally relevant genetic variants of TGF-beta1 are associated with chronic nonalcoholic pancreatitis. METHODS: The promotor as well as exon 1 variants of the TGF-beta1 gene (G-800A, Leu10Pro and Arg25Pro) were investigated. Forty-two CP patients with a family history of nonalcoholic chronic pancreatitis (group A) and 88 patients without a family history of nonalcoholic chronic pancreatitis (group B) were studied. One hundred blood donors served as controls (group C). RESULTS: The allelic frequencies of G-800A, Leu10Pro and Arg25Pro were 12, 38 and 6% in group A; 7, 40 and 6% in group B and 12, 29 and 3% in group C, respectively. The differences were not significant. CONCLUSION: Functionally relevant genetic variants of the TGF-beta1 gene are not associated with nonalcoholic chronic pancreatitis.

Pseudomonas pneumonia-mediated sepsis induces expression of pancreatitis-associated protein-I in rat pancreas.

Severe impairment of exocrine pancreatic secretion has recently been demonstrated in a clinical study in sepsis and septic shock patients. The purpose of this study was to further evaluate involvement of the pancreas in the acute phase reaction in sepsis. Using a normotensive rat model of Pseudomonas pneumonia-induced sepsis, we assessed the expression of PAP-I, amylase and trypsinogen mRNA, PAPI protein levels, and cytokine expression in the pancreas by Northern and Western blot analysis and RT-M PCR, respectively. Presence of several well-established features of pancreatitis in sepsis-induced animals were examined by biochemical and histopathological methods as well as by a determination of both water and myeloperoxidase content. Sepsis resulted in an up-regulation of PAP-I gene expression and increase in its protein level in pancreas while the mRNA levels of amylase and trypsinogen were down-regulated. Differences in the pancreatic cytokine expression, serum amylase and serum lipase levels, the occurrence of pancreatic edema as well as the severity of inflammatory infiltration and necrosis were not significantly different between sham and pneumonia groups. Acinar cells showed increased vacuolization in pneumonia animals 24 hours after the treatment. These findings demonstrate that the pancreas is actively involved in the acute phase reaction in sepsis of remote origin. This involvement occurs without concomitant biochemical and histopathologic alterations observed in pancreatitis. Taken all together, these features are indicative of a sepsis-specific dysfunction of the pancreas.

The stress response of the exocrine pancreas.

Most attacks of acute pancreatitis display a self-limiting course. This suggests that pancreatic acinar cells may be able to protect themselves against cellular injury thus preventing further progression of the disease. In this review we describe several genes overexpressed in acute experimental pancreatitis which take part in the pancreatic stress response. We discuss the possible function of the pancreatitis-associated protein 1, the small nuclear protein p8, the glycoprotein clusterin, different heat shock proteins, the p53-dependent stress proteins TP53INP1alpha and TP53INP1beta, the vacuole membrane protein-1, as well as the interferon-inducible protein-15, the antiproliferative p53-dependent protein PC3/TIS21/BTG2, and the pancreatitis-induced protein-49. The implications of these proteins in pathophysiological processes like apoptosis regulation, regeneration, cell cycle and growth control, regulation of inflammation, and vacuole formation are discussed. Study of the function of stress proteins expressed in response to pancreatitis could widen our understanding of the pathophysiology of the disease and enable us to develop new rational therapeutic strategies.

Clusterin protects the lung from leukocyte-induced injury.

Clusterin (CLU) is a multifunctional 75- to 80-kDa glycoprotein that is upregulated during cellular stress and might represent a defense mechanism during local cellular damage. Mechanisms discussed are antiapoptotic, antioxidative, and anticomplement properties as well as chaperone-like features protecting stressed proteins. The aim of this study was to investigate potential protective effects of CLU on pulmonary vasculature after in situ PMN activation in isolated rabbit lungs. The experiments were performed on 24 isolated and ventilated rabbit lungs that were perfused with 200 mL of Krebs-Henseleit-10% blood buffer with a constant flow of 150 mL/min in a recirculating system. It was tested whether pretreatment with CLU (2.5 microg/ml; n = 8) or catalase (CAT, 5000 U/ml; n = 8) before N-formyl-Met-Leu-Phe (fMLP; 10(-8) M) injection influenced pulmonary artery pressure (PAP) peak airway pressures (PAW) and edema formation as compared with controls (n = 8). Baseline values of PAP were 9-11 mmHg and PAW 11-13 cm H2O. Application of fMLP resulted in an acute significant (P < 0.01) increase of PAP (48 +/- 29 mmHg) within 2 min in the control group and PAW increased to 35 +/- 7 cm H2O within 30 min. Pretreatment with CLU completely suppressed the PAP and PAW response as a result of the fMLP challenge (P < 0.001), whereas a transient PAW increase up to 27 +/- 15 mmHg was observed after CAT. Complement factor C3a release was suppressed by CAT, whereas CLU blocked the complement cascade at the level of C5b-9 formation. Moreover, generation of thromboxane A(2) was reduced after CLU and CAT. Lung edema occurred in the fMLP group but was absent (P < 0.001) after CLU and CAT treatment. Both CLU and CAT prevented fMLP-induced lung injury. Stabilizing effects of CLU, point towards complement regulating features at the level of the terminal complement sequence. Elevated levels of CLU during inflammation could reflect a compensatory organ protective mechanism. Further studies are required to elucidate the clinical impact of the observed organ-protective properties of CLU.

The course of genetically determined chronic pancreatitis.

CONTEXT: The clinical course of chronic pancreatitis in patients with mutations of cationic trypsinogen and the trypsin inhibitor SPINK1 has not yet been characterized. SETTING: Cationic trypsinogen (PRSS1) and the serine protease inhibitor, Kazal type 1 (SPINK1), were analyzed in patients with pancreatitis of unclear origin. PATIENTS: Eighty subjects with trypsinogen mutations (21x N29I, 59x R122H) and 59 patients with the SPINK1 N34S variant (11 homozygous, 48 heterozygous) were included in the study. MAIN OUTCOME MEASURES: In patients with mutations of PRSS1 (N29I, R122H) and SPINK1 (N34S) the parameters such as calcification, dilatation of the main pancreatic duct, diabetes mellitus, hospital treatments, and surgery were recorded. DESIGN: Case control studies were performed to compare both mutational groups, and the follow-up time served as a matching criterion. The Kaplan-Meier analysis was used to estimate the time course of the symptoms. RESULTS: Ten years after the onset of the disease, the probability (+/-SE) of symptoms in patients with PRSS1 mutations was as follows: 1st hospital stay: 86+/-4%; calcification: 21+/-4%; duct dilatation: 26+/-9%; surgery: 19+/-5%; diabetes: 6+/-5%. After 25 years, we found the following data: 1st hospital stay: 96+/-3%; calcification: 38+/-8%; duct dilatation: 38+/-8%; surgery: 37+/-10%; diabetes: 28+/-8%. A case-control-study of 38 pairs of patients with either PRSS1 or SPINK1 mutations showed that the probability of duct dilatation, diabetes and calcification was slightly higher in patients having a SPINK1 mutation. There was no difference between those subjects with a homozygous or heterozygous SPINK1 mutation. In comparison to alcoholic chronic pancreatitis patients, the PRSS1 associated disease revealed a lower frequency of calcification and diabetes. CONCLUSIONS: The progression of chronic pancreatitis was slightly more rapid in patients with SPINK1 mutations than in patients with cationic trypsinogen mutations, but was much less than in those having alcoholic chronic pancreatitis.

Evaluation of Pankrin, a new serum test for diagnosis of acute pancreatitis.

AIM: Evaluation of a new serum test for diagnosis of acute pancreatitis. PATIENTS AND METHODS: One hundred and sixty-three patients presenting with acute abdominal pain were included into the study. Acute pancreatitis was diagnosed by CT or ultrasound. Serum samples were taken 0-1 days, 2-3 days, and 4-5 days after onset of symptoms and C-reactive protein, lipase, elastase, and amylase were determined. As a further parameter, Pankrin, a newly available kit for the measurement of a mixture of elastase and other pancreatic secretory proteins was used. As control, serum from 558 apparently healthy blood donors was analysed. The receiver operator characteristics (ROC) and the areas under the curves (AUC) were calculated for each individual test. RESULTS: In Western blot analysis the antibodies of the Pankrin assay detected the majority of protein bands in human pancreatic juice. In blood donors, the median value of Pankrin was 88 U/ml (range 14-316 U/ml). In 16 from 163 patients with acute abdominal pain, acute pancreatitis was diagnosed and the median Pankrin level in samples collected on days 0-1 was 345 U/ml (range 220-518 U/ml, p<0.0001). In those patients with abdominal pain but without pancreatitis, the median was 116 U/ml (range 17-396 U/ml). The ROC-curves for amylase, lipase, elastase, and Pankrin from samples collected after 0-1 days were similar (area under the curves (AUC) >0.98). After 2-3 days, the AUC of all markers decreased (AUC 0.80-0.89) and after 4-5 days the AUC of Pankrin (0.85) was higher than all other parameters. CONCLUSION: In those patients with abdominal pain, who present several days after onset of pain, the new serum test for pancreatitis, Pankrin, could be of help to improve the diagnosis of pancreatitis.

Cathepsin B cleavage of the trypsinogen activation peptide.

BACKGROUND: Cathepsin B is thought to play a central role in intrapancreatic trypsinogen activation and the onset of pancreatitis. A recent investigation of the cathepsin B mediated activability of wildtype trypsinogen and their mutations N29I, N29T and R122H, which are associated to hereditary pancreatitis, revealed no differences. This action seems to be restricted to the K23-I24 peptide bond, which is the trypsinogen activation bond. Here we investigated the influence of the mutations D22G and K23R of the trypsinogen activation peptide on the cleavability by cathepsin B. METHODS: To investigate the functional impact of the TAP mutations on cathepsin B mediated cleavage of the trypsinogen activating K23-I24 bond, the corresponding peptides pWT, APFDDDDKIVGG; pD22G, APFDDDGKIVGG; and pK23R, APFDDDDRIVGG were digested with cathepsin B for 30 min at pH 3.8 and 5.0, and the fragments were analysed by high-performance liquid chromatography. RESULTS: Without cathepsin B, less than 1 % of the peptides were hydrolysed. After a 30-minute digestion with cathepsin B at pH 5, 96% of pWT, 48% of pK23R, but only 2.4% of pD22G were hydrolysed. At pH 3.8, the cathepsin B cleavage of pWT and pK23R was less than at pH 5, whereas the cleavage of pD22G was completely inhibited. CONCLUSIONS: Cathepsin B mediated trypsinogen activation seems not to be a crucial pathogenic step in hereditary pancreatitis patients with the trypsinogen mutations D22G and K23R.

The HMG-I/Y-related protein p8 binds to p300 and Pax2 trans-activation domain-interacting protein to regulate the trans-activation activity of the Pax2A and Pax2B transcription factors on the glucagon gene promoter.

p8 is a nuclear DNA-binding protein, which was identified because its expression is strongly activated in response to several stresses. Biochemical and biophysical studies revealed that despite a weak sequence homology p8 is an HMG-I/Y-like protein, suggesting that p8 may be involved in transcription regulation. Results reported here strongly support this hypothesis. Using a pull-down approach, we found that p8 interacts with the general co-activator p300. We also found that, similar to the HMG proteins, p300 was able to acetylate recombinant p8 in vitro, although the significance of such modification remains to be determined. Then a screening by the two-hybrid system, using p8 as bait, allowed us to identify the Pax2 trans-activation domain-interacting protein (PTIP) as another partner of p8. Transient transfection studies revealed that PTIP is a strong inhibitor of the trans-activation activities of Pax2A and Pax2B on the glucagon gene promoter, which was chosen as a model because it is a target of the Pax2A and Pax2B transcription factors. This effect is completely abolished by co-transfection of p8 in glucagon-producing InRIG9 cells, indicating that p8 binding to PTIP prevents inhibition of the glucagon gene promoter. This was not observed in NIH3T3 fibroblasts that do not express glucagon. Finally, expression of p8 enhances the effect of p300 on Pax2A and Pax2B trans-activation of the glucagon gene promoter. These observations suggest that in glucagon-producing cells p8 is a positive cofactor of the activation of the glucagon gene promoter by Pax2A and Pax2B, both by recruiting the p300 cofactor to increase the Pax2A and Pax2B activities and by binding the Pax2-interacting protein PTIP to suppress its inhibition.