The renal and glomerular dynamic effects of combining a thiazide and angiotensin antagonists has not been reported. The present study was designed to examine the effects of hydrochlorothiazide (HCTZ) alone or in combination with an angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin II type-1 receptor blocker (ARB) on renal hemodynamics, glomerular dynamics, renal function, and renal histopathology in the L-NAME/SHR model. HCTZ (80 mg/kg/day) alone or in combination with enalapril (30 mg/kg/day) or losartan (30mg/kg/day) or enalapril (15 mg/kg/day) plus losartan (15 mg/kg/day) was administered to L-NAME/SHR (5.0±0.10 mg/kg/day) for three weeks. Mean arterial pressure (MAP), total peripheral resistance (TPR), renal plasma flow (RPF), glomerular filtration rate (GFR), glomerular hydrostatic pressure (P_G), afferent (R_A) and efferent (R_E) glomerular arteriolar resistances, single nephron plasma flow (SNPF), single nephron glomerular filtration rate (SNGFR), serum creatinine concentration, 24 hour urinary protein excretion, glomerular (GIS) and arteriolar (AIS) injury scores were determined. HCTZ reduced MAP, TPR, P_G, R_A and R_E (p<0.05, at least) but slightly increased RPF and SNPF associated with reduced serum creatinine concentration, urinary protein excretion, and AIS compared with L-NAME/SHR control. However, the combination of enalapril and/or losartan with HCTZ markedly improved each of these functions. These results demonstrated minor benefits of HCTZ monotherapy and a marked superiority of its combination with enalapril and/or losartan over HCTZ monotherapy on renoprotection in L-NAME/SHR, thereby providing strong evidence of their clinical benefits for hypertensive patients with renal functional impairment.