Vitamin E reduces glomerulosclerosis, restores renal neuronal NOS, and suppresses oxidative stress in the 5/6 nephrectomized rat.

Chronic kidney disease is accompanied by nitric oxide (NO) deficiency and oxidative stress, which contribute to progression. We investigated whether the antioxidant vitamin E could preserve renal function and NO bioavailability and reduce oxidative stress in the 5/6th nephrectomy (NX) rat model. We studied the following three groups of male Sprague-Dawley rats: sham (n = 6), 5/6 NX control (n = 6), and 5/6 NX treated with vitamin E (5,000 IU/kg chow; n = 5). The 5/6 NX group showed increased severity of glomerulosclerosis vs. sham, and this was ameliorated by vitamin E therapy. Both 5/6 NX groups showed similar elevations in plasma creatinine and proteinuria and decreased 24-h creatinine clearance compared with sham. There was increased NADPH-dependent superoxide production in 5/6 NX rats vs. sham that was prevented by vitamin E. Total NO production was similarly reduced in both 5/6 NX groups. There was unchanged abundance of endothelial nitric oxide synthesis (NOS) in renal cortex and medulla and neuronal (n) NOS in medulla. However, in kidney cortex, 5/6 NX rats had lower nNOS abundance than sham, which was restored by vitamin E. An increased plasma asymmetric dimethylarginine occurred with 5/6 NX associated with decreased renal dimethylarginine dimethylaminohydrolase activity and increased type 1 protein arginine methyltransferase expression.

DOCA/NaCl-induced chronic kidney disease: a comparison of renal nitric oxide production in resistant and susceptible rat strains.

Recent studies show nitric oxide (NO) deficiency is both a cause and consequence of chronic kidney disease (CKD). Reduced renal neuronal NO synthase (nNOS) abundance and activity parallel development of CKD with different models in the Sprague-Dawley (SD) rats, whereas Wistar Furth (WF) rats are protected against CKD and show preserved renal NO production. In this study, we compared renal NO in response to DOCA/salt-induced injury between the WF and SD. Studies were conducted on sham WF (n = 6) and SD (n = 6) and uninephrectized (UNX)+75 mg DOCA+1% NaCl (WF n = 9; SD n = 10) rats followed for 5 wk. Kidneys were harvested for Western blot, NOS activity, and histology. Other measurements included creatinine clearance and 24-h total NO production and urinary protein excretion. Absolute values of kidney weight were lower in WF than SD rats that showed similar percent increases with UNX+DOCA/NaCl. Proteinuria and decreased creatinine clearance were present in the SD but not the WF rats following UNX+DOCA/NaCl. Glomerular injury was mild in the WF compared with SD rats that showed many globally damaged glomeruli. Although renal nNOS abundance was decreased in both strains (higher baseline in WF), soluble NOS activity was maintained in the WF but significantly reduced in the SD rats. Renal endothelial NOS abundance and membrane NOS activity were unaffected by treatment. In summary, WF rats showed resistance to UNX+DOCA/NaCl-induced CKD with maintained renal NO production despite mild reduction in nNOS abundance. Further studies are needed to evaluate how WF rats maintain renal NO production despite similar changes in abundance as the vulnerable SD strain.

Resistance to renal damage by chronic nitric oxide synthase inhibition in the Wistar-Furth rat.

Chronic nitric oxide synthase inhibition (NOSI) causes chronic kidney disease (CKD) in the Sprague Dawley (SD) rat. We previously showed that the Wistar-Furth (WF) rats are resistant to several models of CKD and maintain renal nitric oxide (NO) production compared with SD rats, whereas low-dose NOSI caused progression of CKD in WF rats. Here, we evaluate the impact of high-dose chronic NOSI in WF and SD rats, as well as intrarenal responses to an acute pressor dose of NOSI in the normal WF. Rats were given N(G)-nitro-l-arginine methyl ester (l-NAME) (150 and 300 mg/l for 6-10 wk) in the drinking water after an initial bolus tail vein injection. Both strains showed significant reductions in total NO production with chronic l-NAME. SD given 150 mg/l l-NAME for 6 wk developed proteinuria and renal injury, whereas WF rats receiving 150 mg/l l-NAME for 6-10 wk or 300 mg/l for 6 wk developed no proteinuria and minimal renal injury. Blood pressure was significantly elevated with chronic NOSI in both strains but was higher in the SD rat. There was little impact on renal nitric oxide synthase expression with l-NAME, except that cortical endothelial nitric oxide synthase abundance increased in WF after 6 wk (150 mg/l). Micropuncture experiments with acute pressor NOSI resulted in similar increases in systemic blood pressure in SD and WF rats, whereas WF rats showed a much smaller increment in glomerular blood pressure compared with SD rats. In conclusion, WF rats do not develop renal injury after chronic NOSI at, or above, a dose that causes significant injury in the SD rat. This protection may be associated with protection from glomerular hypertension.

Protection against puromycin aminonucleoside-induced chronic renal disease in the Wistar-Furth rat.

The Wistar-Furth (WF) rat is protected against chronic renal disease (CRD) following 5/6th ablation/infarction vs. the Sprague-Dawley (SD) rat, and protection was associated with preserved renal nitric oxide (NO) production. This study examined CRD induced with repeated administration of puromycin aminonucleoside (PAN). SD PAN developed nephrotic range proteinuria (>1 g/24 h), and at 15 wk severe renal injury developed and the glomerular filtration rate (GFR) was reduced to approximately 10% of sham. Total NO production, renal NO synthase (NOS) activity, and renal neuronal (n) and medullary endothelial (e)NOS abundance were reduced in the SD PAN. WF PAN exhibited less severe initial proteinuria (>400 mg/24 h), which abated within weeks, whereas GFR was normal and injury was minimal at 15 wk. Total NO production and renal NOS activity and abundance were significantly elevated compared with SD PAN. NOS mRNA (nNOS, eNOS, and inducible NOS) was not altered in WF, whereas SD showed significant increases in NOS gene expression with PAN. In conclusion, WF showed resistance to a second model of CRD with maintained renal NOS activity compared with SD.

Peroxisome proliferator-activated receptor [gamma] agonist provides superior renal protection versus angiotensin-converting enzyme inhibition in a rat model of type 2 diabetes with obesity.

The inbred obese Zucker (ZDF/Gmi, fa/fa) rat develops severe hyperglycemia and also exhibits severe renal disease. In this study, we compared the relative benefits of long-term treatment with angiotensin-converting enzyme inhibition (ACEI) to a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist. Four groups of obese inbred Zucker rats were studied over a 6-month observation period; untreated animals, rats treated with ACEI alone, rats treated with PPARgamma agonist alone, and rats treated with a combination of ACEI and PPARgamma agonist. PPARgamma agonist treatment normalized plasma glucose and led to massive increases in body weight. Both ACEI and PPARgamma agonist were effective in reducing the proteinuria and glomerular and tubular kidney damage. However, the PPARgamma agonist exerted superior renal protection compared with ACEI, in this model of spontaneously occurring chronic renal disease in the diabetic, obese inbred Zucker rat. Of note, although ACEI lowered blood pressure, there was no difference in glomerular blood pressure in any group at the end of the study. The glomerular filtration rate (GFR) was improved by ACEI with a borderline effect of PPARgamma agonist alone. A mild additive protection on GFR and tubulointerstitial damage was seen with the combination. Based on the literature it is likely that the superior protection by PPARgamma agonist versus glomerular and tubular damage as well as proteinuria extends beyond glycemic and lipidmic control and also reflects direct, protective intrarenal actions of the PPARgamma agonists.