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1.  Arginine and Asymmetric Dimethylarginine in Puromycin Aminonucleoside-Induced Chronic Kidney Disease in the Rat 
American Journal of Nephrology  2011;35(1):40-48.
Background/Aims
Reduced renal L-arginine (L-Arg) synthesis/transport, induction of arginases and increased endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA) will inhibit NO production. This study investigated pathways of L-Arg synthesis/uptake/utilization, ADMA degradation and oxidant/antioxidants in puromycin aminonucleoside (PAN) chronic kidney disease (CKD).
Methods
Rats were given low- (LD) or high-dose (HD) PAN and followed for 11 weeks for proteinuria. BP was measured and blood and tissues were harvested and analyzed for abundance of argininosuccinate synthase (ASS) and lyase (ASL), arginase, cationic amino acid transporter (CAT1) and dimethylargininedimethylaminohydrolase (DDAH) in kidney, cortex, aorta and liver. Arginase and DDAH activity, plasma L-Arg and ADMA, renal pathology and creatinine clearances were also measured.
Results
PAN caused dose-dependent kidney damage and hypertension and creatinine clearance fell in HD-PAN. Renal ASS fell in HD-PAN, renal cortex and aortic ASL and membrane CAT1 fell in both PAN groups. There was no activation of renal arginase, but aortic arginase increased in LD-PAN. Renal DDAH activity fell moderately in LD-PAN and markedly in HD-PAN where hepatic DDAH activity also fell. Plasma L-Arg was unchanged while ADMA rose moderately and dose-dependently with PAN. There were several indices of oxidative stress which was most prominent in HD-PAN.
Conclusion
Reduction in renal ASS/ASL and loss of renal cortex CAT1 compromises renal L-Arg synthesis and release. Loss of aortic CAT1 impairs L-Arg uptake. Increased plasma ADMA was associated with progressive loss of renal DDAH activity. However, loss of renal clearance and falls in hepatic DDAH activity in HD-PAN did not have additive effects on plasma ADMA.
doi:10.1159/000334740
PMCID: PMC3251243  PMID: 22179117
Argininosuccinate synthase; Argininosuccinate lyase; Arginase; Cationic amino acid transporter, CAT1; Dimethylarginine dimethylaminohydrolase, DDAH; Hypertension; Proteinuria; Creatinine clearance; Nitric oxide
2.  Chronic Nitric Oxide Deficiency and Progression of Kidney Disease after Renal Mass Reduction in the C57Bl6 Mouse 
American Journal of Nephrology  2010;32(6):575-580.
Background/Aims
The C57Bl6 mouse is resistant to chronic kidney disease (CKD) induced by reduction of renal mass (RRM). Nitric oxide (NO) deficiency exacerbates CKD progression so this study investigated whether combination of RRM and NO deficiency would render the C57Bl6 mouse vulnerable to CKD.
Methods
We used wild-type (WT) mice with RRM, chronic NO synthase (NOS) inhibition and a combination. Also, endothelial NOS (eNOS) knockout (KO) C57Bl6 mice were studied with and without RRM. Primary endpoints were albuminuria and structural damage.
Results
Both nonselective (+l-NAME) and neuronal NOS ‘selective’ (+7NI) NOS inhibition greatly exacerbated the albuminuria and structural damage seen with RRM in the WT mice; NOS inhibition alone had little effect. The eNOS KO mice showed marked structural damage and significant albuminuria in the shams and RRM produced minimal exacerbation of structural damage although the albuminuria was massively amplified.
Conclusion
These studies demonstrate that the C57Bl6 mouse is rendered vulnerable to RRM-induced CKD when concomitant NO deficiency is produced. This observation supports previous work in CKD-resistant rats and suggests that NO deficiency is required for progression of CKD.
doi:10.1159/000322106
PMCID: PMC2992651  PMID: 21071934
Nitric oxide synthase inhibition; Endothelial NOS knockout; Albuminuria; Creatinine clearance; Renal pathology
3.  Lack of Long-Term Protective Effect of Antioxidant/Anti-Inflammatory Therapy in Transplant-Induced Ischemia/Reperfusion Injury 
American journal of nephrology  2006;26(3):213-217.
Background
Alloantigen-independent factors contribute to long-term damage in renal transplant recipients, likely due to ischemia/reperfusion (I/R) injury at transplantation (Tx). I/R injury promotes oxidative stress and inflammation resulting in endothelial injury.
Methods
In this study we investigated the long-term efficacy (22 weeks) of short-term (10 day) endothelial protection therapy (EP) in ‘optimal’ donor kidneys using the male Fisher 344 rat isograft (ISO) model. ISO-EP kidneys were compared to untreated ISO (ISO-UN) kidneys. EP involved dexamethasone to donor, ex vivo treatment of the kidney with deferoxamine and tempol, and administration to the recipient of l-arginine and tempol for 10 days. Rats were sacrificed 22 weeks following Tx and compared to age-matched, normal controls.
Results
Both groups of ISO Tx rats developed similar renal dysfunction and structural damage and renal NADPH-oxidase-dependent O2− production was similarly elevated in ISO-UN and ISO-EP groups vs. controls. In vitro renal cortex NO synthase (NOS) activity was also similar in ISO-UN and ISO-EP rats, despite lower nNOS and eNOS protein abundance in ISO-EP.
Conclusion
I/R injury-induced late graft dysfunction occurs even when optimal donors are used and when short-term EP treatment is given. Increased renal superoxide production is not prevented by short-term EP therapy.
doi:10.1159/000093587
PMCID: PMC2756816  PMID: 16720982
Antioxidant; Ischemia/reperfusion; Kidney transplant; Nitric oxide

Results 1-3 (3)