Renal pathology and clinical outcomes in patients with primary Sjögren's syndrome (pSS) who underwent kidney biopsy (KB) because of renal impairment are reported. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-four of 7276 patients with pSS underwent KB over 40 years. Patient cases were reviewed by a renal pathologist, nephrologist, and rheumatologist. Presentation, laboratory findings, renal pathology, initial treatment, and therapeutic response were noted. RESULTS: Seventeen patients (17 of 24; 71%) had acute or chronic tubulointerstitial nephritis (TIN) as the primary lesion, with chronic TIN (11 of 17; 65%) the most common presentation. Two had cryoglobulinemic GN. Two had focal segmental glomerulosclerosis. Twenty patients (83%) were initially treated with corticosteroids. In addition, three received rituximab during follow-up. Sixteen were followed after biopsy for more than 12 mo (median 76 mo; range 17 to 192), and 14 of 16 maintained or improved renal function through follow-up. Of the seven patients presenting in stage IV chronic kidney disease, none progressed to stage V with treatment. CONCLUSIONS: This case series supports chronic TIN as the predominant KB finding in patients with renal involvement from pSS and illustrates diverse glomerular lesions. KB should be considered in the clinical evaluation of kidney dysfunction in pSS. Treatment with glucocorticoids or other immunosuppressive agents appears to slow progression of renal disease. Screening for renal involvement in pSS should include urinalysis, serum creatinine, and KB where indicated. KB with characteristic findings (TIN) should be considered as an additional supportive criterion to the classification criteria for pSS because it may affect management and renal outcome.

• MeSH
• biologické markery krev   moč   MeSH
• biopsie MeSH
• časové faktory MeSH
• chronické selhání ledvin etiologie   patologie   prevence a kontrola   MeSH
• dospělí MeSH
• fokálně segmentální glomeruloskleróza etiologie   patologie   MeSH
• glomerulonefritida etiologie   farmakoterapie   patologie   MeSH
• hormony kůry nadledvin terapeutické užití   MeSH
• imunosupresiva terapeutické užití   MeSH
• intersticiální nefritida etiologie   farmakoterapie   patologie   MeSH
• kryoglobulinemie etiologie   farmakoterapie   patologie   MeSH
• ledviny patologie   účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• monoklonální protilátky terapeutické užití   MeSH
• progrese nemoci MeSH
• revmatoidní artritida farmakoterapie   komplikace   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH

In previous studies we observed that inhibition of cyclic 3',5'-nucleotide phosphodiesterase (PDE) isozymes, namely isozyme PDE3, suppresses proliferation of rat renal glomerular mesangial cells in vitro and in vivo. To determine whether activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway coupled to specific PDE isozymes modulates accelerated proliferation of renal epithelial cells, we investigated the effect of selective PDE isozyme inhibition on renal epithelial cell proliferation induced in rats by injection of folic acid (FA). In extracts from suspensions of renal cortical tubules, cAMP was metabolized predominantly by isozyme PDE4; activity of PDE3 was about three times lower. The increase in proliferative activity of renal cortical tissue from FA-injected rats, evaluated by immunostaining with Mib-1 antibody, was limited to tubular epithelial cells. Administration of the PDE3 inhibitors cilostazol or cilostamide together with the PDE4 inhibitor rolipram blocked mitogenic synthesis of DNA, as determined by (3H)-thymidine incorporation into renal cortical DNA, in FA-treated rats. FA injection caused an increase of more than 10-fold in proliferating cell nuclear antigen (PCNA) in renal cortical tissue; administration of the potent PDE3 inhibitor lixazinone or, to a lesser degree, cilostazol suppressed these high PCNA levels, whereas rolipram alone had no effect. The results indicate that FA-stimulated in vivo proliferation of renal tubular epithelial cells is down-regulated by activation of a cAMP-PKA signaling pathway linked to PDE3 isozymes. These observations are consistent with the notion that negative crosstalk between cAMP signaling and mitogen-stimulated signaling pathways regulates mitogenesis of renal cells of different terminal differentiation, including tubular epithelial cells.

• MeSH
• AMP cyklický * metabolismus   MeSH
• buněčné dělení účinky léků   MeSH
• cAMP-fosfodiesterasy * antagonisté a inhibitory   metabolismus   MeSH
• chinazoliny farmakologie   MeSH
• chinolony farmakologie   MeSH
• cyklické nukleotidfosfodiesterasy, typ 3 MeSH
• down regulace fyziologie   MeSH
• inhibitory fosfodiesteras * farmakologie   MeSH
• izoenzymy antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu rattus MeSH
• kyselina listová farmakologie   MeSH
• ledvinové kanálky * cytologie   metabolismus   účinky léků   MeSH
• potkani Sprague-Dawley MeSH
• proliferační antigen buněčného jádra analýza   MeSH
• proteinkinasy závislé na cyklickém AMP metabolismus   MeSH
• pyrrolidinony farmakologie   MeSH
• rolipram MeSH
• signální transdukce účinky léků   MeSH
• tetrazoly farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

We studied interactions between the mitogen-activated protein kinase (MAPK) signalling pathway and cAMP-protein kinase (PKA) signaling pathway in regulation of mitogenesis of mesangial cells (MC) determined by [3H]thymidine incorporation, with or without added EGF. Forskolin or dibutyryl cAMP strongly (by 60-70%) inhibited [3H]thymidine incorporation into MC. Cilostamide, lixazinone or cilostazol selective inhibitors of cAMP-phosphodiesterase (PDE) isozyme PDE-III, inhibited mitogenesis to similar extent as forskolin and DBcAMP and activated in situ PKA, but without detectable increase in cAMP levels. Cilostamide and cilostazol were more than three times more effective at inhibiting mesangial mitogenesis than rolipram and denbufylline, inhibitors of isozyme PDE-IV, even though PDE-IV was two times more abundant in MC than was PDE-III. On the other hand, when incubated with forskolin, rolipram-enhanced cAMP accumulation was far greater (10-100x) than with cilostamide. EGF increased MAPK activity (+300%); PDE isozyme inhibitors which suppressed mitogenesis also inhibited MAPK. PDE isozyme inhibitors also suppressed PDGF-stimulated MC proliferation. We conclude that cAMP inhibits the mitogen-dependent MAPK-signaling pathway probably by decreasing the activity of Raf-1 due to PKA-catalyzed phosphorylation. Further, we surmise that minor increase in the cAMP pool metabolized by PDE-III is intimately related to regulation of mesangial proliferation. Thus, PDE isozyme inhibitors have the potential to suppress MC proliferation by a focused effect upon signaling pathways.

• MeSH
• cAMP-fosfodiesterasy * antagonisté a inhibitory   MeSH
• chinolony farmakologie   MeSH
• destičkový růstový faktor farmakologie   MeSH
• epidermální růstový faktor farmakologie   MeSH
• glomerulární mesangium cytologie   enzymologie   účinky léků   MeSH
• izoenzymy * antagonisté a inhibitory   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• potkani Sprague-Dawley MeSH
• proteinkinasy závislé na cyklickém AMP * fyziologie   MeSH
• proteinkinasy závislé na vápníku a kalmodulinu metabolismus   MeSH
• pyrrolidinony farmakologie   MeSH
• rolipram MeSH
• thymidin metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH