Role Of Transforming Growth Factor-betal In Pathogenesis Of Human Autosomal Dominant Polycystic Kidney Disease

Background: Transforming growth factor-betal (TGF-betal) is a major profibrotic cytokine involved in many renal diseases.Tubulointerstitial fibrosis is a hallmark feature of human autosomal-dominant polycystic kidney disease (ADPKD) which impairs renal function in varying degrees, with end-stage renal disease (ESRD) occurring in approximately 50% of affected individuals. There are few studies reporting the role of TGF-betal in human ADPKD.OBJECTIVE: To investigate characteristic expression of TGF-beta(l),TGF-beta receptors types I, types II ,CTGF in ADPKD and clarify pathogenesis of TGF-betal in the development and progression of human ADPKD. METHODS: Sixty-five ADPKD patients underwent history taking, physical examination, blood pressure measurement, blood and urine chemistries, renal clearance, abdominal ultrasonography. Renal volumes were determined by ultrasound imaging. Cyst fluid, and urinary and plasma TGF-beta(l) levels were determined by ELISA in 39 ADPKD patients. The results were compared with those of normal subjects and of patients with simple renal cyst.TGF-beta(l), TGF-beta receptors types I, types II, CTGF mRNAs and proteins in the kidneys were examined by in situ hybridization and immunohistochemistry. The relationship between the above fibrosing-associated indicators with the degree of interstitial fibrosis, clinical presentation and prognosis of renal function impairment were analyzed. RESULTS: Plasma TGF-beta(l) in ADPKD was significantly higher compared to those of normal subjects (15.12 ?8.53ng/ml vs 5.41 ?1.31ng/ml,P<0.01). There were no differences in urine TGF-beta(l) level between ADPKD group (0.35 + 0.25 ng/mg ?creatinine) , simple renal cyst group (0.48 + 0.31 ng/mg ?creatinine) and normal subjects ( 0.51+0.21 ng/mg ?creatinine) (p>0.1). There was no significant difference in cyst fluid TGF-beta(l) in ADPKD and simple renal cyst (0.31 ?.21 ng/ml vs 0.53 + 0.13 ng/ml, p=0.65). Expression of TGF-beta(l), TGF-beta receptors types I, types II, CTGF mRNAs and proteins in the kidneys of ADPKD were significantly higher than those of the normal subjects (p<0.05). Expression of TGF-beta(l), TGF-beta receptors types I, types II ,CTGF mRNAs and proteins was upregulatedin fibroticinterstitia, tubular epithelial cells and some sclerotic glomeruli. In cyst lining-epitheliar cells and vessel smooth muscle cells, the positive signals were most obvious. The degree of interstitial fibrosis was significantly correlated with TGF-beta(l) mRNAs (r=0.51, P = 0.001) and proteins (r=0.52, P=0.01) , and also significantly correlated with CTGF mRNAs (r=0.53, P = 0.005) and proteins (r=0.49, P=0.003) too. The degree of GFR was significantly correlated with renal volume (r= -0.51, PO.01), but not with TGF-beta(l) levels in urinary (r=-0.08, P=0.03) or plasma (r=0.006, p<0.01). With the enlargement of the renal volume, abdominal compression, chronic pain and gross hematuria increased rapidly. CONCLUSIONS: The results of our studies suggest that circulating and local produced TGF-beta(l) have a role in the development of interstitial fibrosis and renal failure in ADPKD. Renal volume measurement rather TGF-beta(l) level in body fluid is useful for assessing of renal function and monitoring progression of ADPKD.