CLINICAL STUDY Urinary messenger RNA expression of podocyte-associated molecules in patients with diabetic nephropathy treated by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker Gang Wang 1 , Fernand Mac-Moune Lai 2 , Ka-Bik Lai 1 , Kai-Ming Chow 1 , Bonnie Ching-Ha Kwan 1 , Philip Kam-Tao Li 1 and Cheuk-Chun Szeto 1 Departments of 1 Medicine and Therapeutics and 2 Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese Universityof Hong Kong, Shatin, NT, Hong Kong, China (Correspondence should be addressed to C-C Szeto; Email: ccszeto@cuhk.edu.hk) Abstract Background: Podocyte injury and its subsequent loss in urine play an important role in the pathogenesis of diabetic nephropathy; blockade of the renin–angiotensin system may ameliorate the damage. Methods: In a non-randomized setting, we studied 71 patients with diabetic nephropathy on a stable dose of angiotensin-converting enzyme inhibitor (ACEI). In 37 patients, angiotensin receptor blocker (ARB) was added (the combination group); ACEI alone was continued in the other 34 (the control group). The mRNA expressions of nephrin, podocin, and synaptopodin in urinary sediment were measured at 0 and 12 weeks. Results: Baseline glomerular filtration rate (GFR) correlated with the urinary expression of nephrin (rZ0.320, PZ0.007), podocin (rZ0.336, PZ0.004), and synaptopodin (rZ0.350, PZ0.003). After adjusting for the baseline expression, the combination group had a significantly lower urinary synaptopodin expression (7.49 (95% confidence interval CI, 0.62–115.29) vs 14.83 (95% CI, 1.03– 241.43), PZ0.026) than the control group after 12 weeks of treatment. The percentage change in urinary podocin expression over 12 weeks of treatment had a modest correlation with the rate of GFR decline in 1 year (rZK0.243, PZ0.041). Conclusion: In patients with diabetic nephropathy, urinary mRNA expression of podocyte markers correlated with baseline renal function. Urinary expression of synaptopodin was lower after 12 weeks of ACEI and ARB combination therapy. Our result suggests that serial measurement of urinary podocyte markers may have a value for the monitoring of therapeutic response. European Journal of Endocrinology 158 317–322 Introduction Diabetic nephropathy is the leading cause of end-stage renal disease (1). It is characterized by persistent proteinuria, unremitting renal function decline, and increased cardiovascular morbidity and mortality (2). The renin–angiotensin system (RAS), especially local renal RAS activation, has been recognized to play a key role in the pathogenesis of diabetic nephropathy (3). Blockade of the RAS is currently the standard therapy in the treatment of diabetic nephropathy (4). Dual blockade of RAS by angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) offers additional renoprotective effect when compared with monotherapy by either agent alone (5). Blood pressure, proteinuria, serum creatinine, and glomerular filtration rate (GFR) are commonly used for the clinical monitoring of diabetic nephropathy and its therapeutic response to RAS blockade. However, none of them is entirely satisfactory. Recent studies showed that podocyte injury, an important pathogenetic process of diabetic nephropathy (6), might be a more sensitive means to assess the degree of glomerular damage (7) as well as the response to blockade of RAS (8–10). However, clinical application of this strategy is limited because renal biopsy and immunohistological tech- niques are required. In the last few years, with the development of reliable RNA extraction techniques from urinary sediment and RT real-time quantitative PCR (RT-QPCR), measurement of mRNA expression in urinary sediment has become an emerging tool for the study of kidney diseases (11). Our previous cross- sectional study has showed that the mRNA expression of podocyte markers, such as nephrin, podocin, and synaptopodin, in urinary sediment is increased in patients with diabetic nephropathy (12). The objective of the present study was to examine the change in gene expression of podocyte-associated molecules in the European Journal of Endocrinology (2008) 158 317–322 ISSN 0804-4643 q 2008 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0708 Online version via www.eje-online.org