The expression of Bartter/Gitelman syndrome clinical pathological analysis and macula densa COX-2 patients
|School||Beijing Union Medical College|
|Keywords||Gitelman syndrome(GS) Bartter syndrome(BS) SLC12A3 cyclooxygenase-2(COX-2) Renin-Angiotensin-aldosterone System(RAS) glomerulotubular imbalance|
BackgroundBartter syndrome(BS) and Gitelman syndrome(GS) are similar hereditary hypokalaemic salt-losing tubulopathies(SLTs). They have different pathogenic gene. The gene detective is needed to confirm the diagnosis. COX-2protein and mRNA expression has been observed in the macula densa (MD) cells in patients with BS.But weather COX-2involved in the activation of rennin-angiotensin systerm (RAS) of GS is still unknown, although the PGE2level of urine in these patients was normal.ObjectiveThe purpose of this study was to to identify the mutations of SLC12A3gene in Gitelman syndrome patients, to observe the relationship between the renin/COX-2expression of Juxtaglomerular apparatus (JGA) and the plasm renin activity(PRA) of SLTs patients.MethodsClinical data of36patients who hospitalized in Peking Union Medical College Hospital (PUMCH) with hereditary hypokalaemic SLTs were collected and analyzed. SLC12A3gene of11patients from9unrelated families (3femals from one family, two generations) were analyzed by direct sequencing. The clinical features and genotype of heterozygous and compound heterozygous/homozygous were compared. The PRA, Angll, aldosterone were measured by RI. The kidney biopsy were done in24patients,5of them were confirmed as GS by gene detective. Renin and COX-2protein expression of the Juxtaglomerular apparatus(JGA) were measured by immunohistochemistry. The control group was5patients with minimal change of the kidney pathology and without hypertension.Results1. Eight mutations of SLC12A3gene were identified in9patients. Two were novel variants, including one missense mutations:Asn534Lys; one deletion:493～496delACGG. Eight were recurrent mutations:Thr60Met、Thr304Met, Arg399Cys, Cys430Gly,Asp486Asn,Ser615Leu and810insATTGGCGTGGTCTCGGTC. The homozygous or heterozygous mutation Thr60Met was found in2of9patients. There were no obviously differences of chinical features and chemical examination between simple heterozygous and compound heterozygous/homozygous. 2. The common symptoms were limbs fatigue (94%), palpitations or chest tightness (56%), tetany (47%), limb numbness (42%). Plasma renin concentration and Ang II was obviously increased in these patients. Plasm magnesium and urinary calcium concentration have a good positive correlation. There was no gender differences of chemical examinations except urinary potassium and chlorides.1/3patients were companied with the subclinical hypothyroidism (31%) or impaired glucose tolerance (30%). Abnormal ECG changes were observed in13cases.3. Juxtaglomerular apparatus hyperplasia was observed in most of the hereditary hypokalaemic SLTs patients (92%). Vacuolar degeneration of the renal epithelial tubular cells was common. In some cases, chronic index such as focal interstitial fibrosis, inflammatory cell infiltration were also observed.4. Renin expression in JG cells and COX-2expression in MD cells were obviously higher in the hereditary hypokalaemic SLTs patients (including5Gitelman syndrome patients) than control, which have good relationship with the PRA plasm Ang II.Conclusion1. The incidence of Gitelman syndrome may be higher than expected. Gene analysis is essential to diagnose Gitelman syndrome.2. Hypokalaemia-related symptoms are the most prominent clinical manifestations of hereditary hypokalaemic SLTs. In these patients, plasma magnesium and urinary calcium have a good positive correlation.3. The JGA hyperplasia was observed in more than90%of these patients, which have good relationship with the PRA and plasma Ang Ⅱ.4. The COX-2expression in MD cells may be involved in the RAS activation in GS patients.