الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
 |  | from | 124 |  |  |
| | | from | 124 | | |
Abstract
Living kidney transplantation is considered as the treatment of choice for ESRD patients. However, this treatment imposed the risk of an unnecessary additional surgery in the donors. Kidney donors demonstrated decreased GFR and creatinine clearance; with manifest albuminuria and increased serum creatinine shortly post-nephrectomy. The rate of albuminuria increased with time after donation, and was associated with renal disease progression, cardiac hypertrophy and cardiovascular diseases. The reduced kidney function was also often accompanied by deterioration in glucose metabolism with increased risk of insulin resistance, and disturbed lipid metabolism with hyperlipidemia
The UNX rat model had been used as a reflection to human kidney donors. UNX rats demonstrated progressive renal impairment coupled to dysmetabolism, fat redistribution and renal structural changes. Early studies related these changes to the disturbed haemodynamics occurring in the remaining kidney. This caused shear stress with consequent podocyte injury and proteinuria, mesangial cell activation and secretion of several growth factors. However, recent studies suggested that the renal dysfunction may be also related to the disturbed metabolism that accompanied the disturbed haemodynamics, with lipid deposition and activation of multiple inflammatory and oxidative cascades
Sirtuins are highly conserved NAD+ dependent protein deacetylases, with critical roles in regulating mammalian energy metabolism in response to nutrient signals. SIRT1, as an intracellular energy sensor, has a critical role in many metabolic processes including regulation of lipid metabolism and glucose homeostasis. Moreover, accumulate evidence has demonstrated beneficial effects of SIRT1 as an antioxidant, and in suppression of apoptosis, inflammation and fibrosis.
SIRT1 is highly expressed in medullary tubular cells and moderately expressed in cortical proximal tubular cells. Authors related disease progression in chronic kidney diseases e.g. diabetic nephropathy to the decreased renal SIRT1 expression. Knocked out SIRT1 expression in proximal tubules showed increased albuminuria, while transgenic SIRT1 expression in decreased albuminuria in diabetic mice.
SIRT1 over expression or activation in renal tissue can decrease renal fibrotic and apoptotic pathways by both effective energy metabolism and modulating inflammatory mediators. Resveratrol, the most common activator of SIRT1 has been shown to ameliorate several types of renal injury, including diabetic nephropathy, drug-induced injury, and ischemia-reperfusion injury in animal models through its antioxidant effect or SIRT1 activation. We examined the renal SIRT1 expression profile following uninephrectomy, and whether resveratrol can reverse some of the associated structural or functional impairments.
The study was conducted on 78 adult male Wistar rats. After a 1-week acclimatization period, rats were weighed and randomly assigned into 3 groups, 26 rats each: 3 months’ group, 5 months’ group and 7 months’ group. Each group was randomly assigned into 3 sub-groups: control group (sham operated rats, n=6), uninephrectomized group (UNX, n=10) and uninephrectomized treated with Resveratrol group (UNX+Res, n=10). Rats in the UNX and UNX+Res groups underwent surgical removal of the right kidney at the start of the experiment. The sham-operated control group was exposed to the same surgical procedure except that the kidney was exposed but not excised. Rats were allowed one week for recovery, after which they were weighed and administered 20 mg/kg/day resveratrol (UNX+Res group) dissolved in 3% DMSO, or equivalent volume of vehicle (UNX group) by daily oral gavage till termination of the experiment 3, 5 or 7 months post-nephrectomy.
One week before termination, 24 hour urine was collected and urine creatinine and protein concentrations were measured. Two days before termination, an IPGTT was carried out after a 12-hour fast. The experiment was terminated, and tissues and plasma were harvested for different subgroups from each group at 3, 5 and 7 months post-surgery. The left kidney was harvested and weighed, and CRG was calculated. Half the kidney was frozen and homogenized for measuring renal MDA level and SIRT1 immunobloting, and the other half was fixed with formalin for histological examination and SIRT1 immunostaining. The hearts were also harvested and weighed as an index of cardiac hypertrophy. Renal function tests, serum electrolytes and lipid profile were also measured in terminal fasting serum samples. Serum non-HDL-C and atherogenic index were calculated.
Results from the present study showed that UNX triggered renal hypertrophy of the remaining kidney with subsequent development of fibrotic changes and impairment of kidney functions characteristic of chronic kidney disease. These changes were associated with reduction of renal SIRT1 protein expression and an increase in oxidative stress marker, MDA, in the kidney. There was some sort of dysmetabolism, manifested by dyslipidemia, increased atherogenic index and impaired glucose tolerance progressed to elevated fasting blood glucose levels at 7 months post-nephrectomy.
Resveratrol administration greatly ameliorated the renal functional and structural changes that followed UNX. Renal SIRT1 expression was restored at the 3 time end-points and MDA levels was decreased even lower than controls. This was associated with amelioration of renal and cardiac hypertrophy and suppression of renal fibrotic changes. Serum urea, creatinine and sodium, and albuminuria decreased significantly especially at 7 months post-nephrectomy. The glucose tolerance and lipid profile were restored to control values especially in the 7 months’ group. In conclusion, deficient SIRT1 expression is associated with structural and metabolic dysregulation observed in UNX rats and resveratrol, a SIRT1 activator, markedly attenuated these changes and therefore, it could be a potentially beneficial adjuvant therapy in human kidney donors.