| PART 1: Renal Protection of Rosiglitazone in Two-Kidney-One-Clip Hypertensive RatsObjective: Though hypertension has been the second main cause of end-stage renal disease, there're problems unresolved by the exiting measures yet. Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily. Thiazolidinediones (TZDs), kinds of synthetic ligands, have beneficial effects on diabetic nephropathy by improving insulin sensibility and lipid metabolism. The beneficial effect also reported in nondiabetic rats. Though reduction of blood pressure has been found in many models or patients treated with TZDs, there're nearly no reports about the effect on hypertensive renal injury. We observed renal protection of rosiglitazone in hypertensive rats and studied the relationship between renal protection and metabolism modulating and reduction of blood pressure.Methods: Two-kidney-one-clip models were made with male Wistar rats (about 250g). Those blood pressure equal to or higher than 160mmHg were enrolled and divided randomly into 6 groups as follows: The positive control group (CONT), the common-therapy group (R&D, received drug with reserpine and dihydralazine in its ingredient), the regular-dose rosiglitazone group (RRGL, received 5mg.kg-1.d-1 rosiglitazone), the lisinopril group (LSPL), the coadministration group (LSPL+RRGL, received lisinopril and rosiglitazone) and the large-dose rosiglitazone group(LRGL, received 20mg.kg-1.d-1 rosiglitazone). There're 8 rats in each group. Eight sham rats were fed as negative controls. Animals were monitored and sacrificed at 10th week. Blood, urine and right kidneys (without clips) were harvested for biochemical, morphologic and molecular analysis. Results: Body weights of rats in each group had no significant differences over time. Rats in every treated groups, except those in RRGL group, had significant lower blood pressure than those in CONT group from week 2. Blood pressure in LRGLgroup was lower compared with that in RRGL group (P<0.05), no significant difference with that in R&D group and higher than that in LSPL and LSPL+RRGL group(P<0.05). The LSPL and LSPL+RRGL groups had statistically equal blood pressure. Serum creatinine, blood glucose, and serum cholesterol were statistically equal in all groups both before and after the study. So did the level of serum triglyceride before the study. At 10th week, the level of serum triglyceride in CONT group was higher than the treated groups, but no significant differences were found among treated groups. Before the study, urinary protein excretion rate in SHAM group was lower than that in CONT group (8.93±4.46 vs.l9.77±9.33 mg/24h, P<0.01). But that among hypertensive groups weren't statistically different. At 10th week, rats in SHAM group had lower urinary protein excretion rate, glomerular injury score and wall-to-lumen ratio of arteriole than those in CONT group (9.42±1.28 vs. 44.60± 17.40 mg/24h, 4.61± 1.91 vs. 60.85±33.05, 1.39±0.37 vs. 2.33±1.01, P<0.01) . These three indexes of rats in RRGL group are also lower than those in CONT group (26.48±7.57 vs. 44.60±17.40 mg/24h, 29.65±6.85 vs. 60.85±33.05, P<0.05; 1.75±0.46 vs. 2.33±1.01, P<0.01). Urinary protein excretion rate, glomerular injury score and wall-to-lumen ratio of arteriole in LRGL group were lower compared with both RRGL group (16.78±3.50 vs. 26.48±7.57 mg/24h, 18.04±7.76 vs. 29.65±6.85, P<0.01; 1.57±0.38 vs. 1.75±0.46, P>0.05) and R&D group (16.78±3.50 vs. 27.94±12.79 mg/24h, 18.04±7.76 vs. 27.92±6.39, 1.57±0.38 vs. 2.16±0.90, P<0.05). All of the three indexes were lower in LSPL+RRGL than LSPL groups (13.33±4.59 vs. 13.81±4.09 mg/24h, 8.04±l. 69 vs. 10.66±2.70, 1.47±0.41 vs. 1.70±0.62), but only difference of glomerular injury score was significant.Conclusion: Our results show that hypertensive renal injury is characteristic of increase of urinary protein excretion rate and morphological changes, which are ahead of increase of serum creatinine. And we demonstrate in vivo that rosiglitazone has modest effect of reduction of blood pressure in two-kidney-one-clip hypertensive rats and can protects the kidneys from hypertensive injury, including decreasingurinary protein excretion rate and alleviating pathological changes. The beneficial effect seems some dose-effect relationship and dose not completely depend on the metabolism modulating and reduction of blood pressure. The results also indicate that coadministration of rosiglitazone and lisinopril is superior to lisinopril alone in the protection of glomeruli from hypertensive injury. No side effects were observed , such as edema, weight gain etc.PART 2: The Involved Mechanisms in Renal Protection ofRcsiglitazone in Two-Kidney-One- Clip Hypertensive RatsObjective: Previous studies demonstrated thiazolidinediones (TZDs) have renal protection effect not only in type 2 diabetes, obesities, but also in some models without metabolic mechanism such as 5/6 nephrectomy rats and two-kidney-one-clip hypertensive rats. Studies also indicated that the beneficial effect is not completely dependent on improved glucose and lipid metabolism and reduction of blood pressure. We discovered some moleculobiological mechanisms what must be involved in the renal protection of rosiglitazone in two-kidney-one-clip hypertensive rats.Methods: The surgery, screening, feeding, grouping, monitoring and sacrificing of animals were finished as Part 1. Reverse tanscriptase-PCR was used to detect the mRNA of FN, TGFβ, PAI-1, AT1R, AT2R, VEGF, VEGFR-1, VEGFR-2 and PPARγ in the cortexes of undipped right kidneys. TGFβ, hypoxyprobe, VEGF, VEGFR-2 and PPARγ were also identified by immunohistochemistry. Results: Compared with SHAM group, mRNA of FN, TGFβ, PAI-1, VEGF, VEGFR-1, VEGFR-2, PPARy in CONT group were up-regulated, while that of AT1R, AT2R were down-regulaed. Immunostaining of hypoxyprobe showed significant hypoxia in the cortexes of undipped right kidneys of CONT group. Intensely expression of VEGF, VEGFR-2 were observed in CONT group, esp. intubules, collecting ducts and suffering glomeruli, which were paralleled with the distribution of hypoxia. Up-regulated expression of PPARγ was also detected in CONT group, which was predominantly in the glomeruli. The RRGL group had weaker expression of FN, TGFβ, PAI-1, AT1R, VEGF, VEGFR-1, VEGFR-2, PPARy, more intense expression of AT2R and improved oxygen supply compared with CONT group. Though with the similar level of blood pressure, blood glucose and lipid, the effects of LRGL were stronger than R&D. And coadministration rosiglitazone and lisinopril stronger than lisinopril alone.Conclusion: Our study suggested rosiglitazone must inhibit the expression of FN, TGF β and PAI-　. Rosiglitazone may also down-regulate the expression and AT1R, VEGF, VEGFR-1, VEGFR-2, up-regulate the expression of AT2R and improve oxygen supply. All of the above mechanisms may be involved in the renal protection of rosiglitazone in two-kidney-one-clip hypertensive rats and be hemodynamics-independent in some extent. Whether the effects are wholly PPARy-dependent is yet unknown.PART 3: Cross-sectional Study of Hypertension in PatientsUndergoing Renal BiopsyObjective: To survey the state and treatment of hypertension in patients undergoingrenal biopsy and instruct clinical diagnosis and treatment.Methods: Medical records of 295 patients undergoing renal biopsy were studiedretrospectively and cross-sectioally.Results: There were high prevalence of hypertension in patients undergoing renalbiopsy, especially that with chronic kidney disease, 54.9% and 63.3% respectively.The prevalence of hypertension secondary to renal parenchymatous diseases ishigher in this group, 25.9% in all of the patients and 26.3% in patients with chronickidney diseases. Varied kidney diseases can be concomitant with hypertension. Both...
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