Browsing by Author "Alhamamah, Mohammed Ali Fahad"
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- ItemRestrictedMolecular pharmacological studies on renal sodium/glucose co-transporters inhibitors(Saudi Digital Library, 2017) Alhamamah, Mohammed Ali Fahad; Kandeel, MahmoudThe sodium/glucose co-transporter (SGLT) inhibitors are new potent antdiabetic drugs by acting on glucose transport system in kidneys. Every day, the kidneys almost return about 180 grams of sugar into the body by reabsorption in the proximal convoluted tubules. SGLTs share in glucose reabsorption by moving glucose into the interior of renal cells. Therefore, inhibition of SGLTs will lead to marked loss of glucose into urine and aid in the control of hyperglycemia regardless the status of insulin secretion or peripheral resistance to insulin actions. Since nephropathy is a common sequence of diabetic complications, it is not well known whether transient, moderate or persistent renal damage events will alter the expression levels of SGLT2 and affect the antidiabetic efficiency of SGLT inhibitors. In this work, the expression levels of SGLT2 as well as the pharmacological actions of SGLT inhibitor Dapagliflozin (DAPA) were evaluated under different renal damage and diabetic conditions. The range of the induced pathological states in this study included 1) acute phase of moderate renal damage 2) late renal recovery after mild or moderate renal damage event 3) renal damaged diabetic conditions and 4) nephropathic conditions after nontreated diabetes mellitus. Results indicated that acute phase of renal damage was associated hyperglycemia, which was not improved by DAPA. DAPA significantly reduced the blood glucose in diabetic rats. While in renal damaged diabetic and diabetic nephropathic rats, there was significant decrease in blood glucose level in comparison with the control group. DAPA induced lower creatinine and uric acid levels in most treatments while there was no significant change in the level of urea among different treatments. The expression levels of SGLT2 were decreased in all types of renal damage, and diabetic conditions. It was found that DAPA significantly decreased the renal pathological lesions. The major recorded pathological lesion includes cellular infiltration, perivascular, periglumerular fibrosis, tubular cystic dilatation, luminar cast, glomerular lesions and hemorrhages. All these lesions were improved in DAPA treated groups. In DAPA treated groups there was lower expression level of apoptosis regulation protein (BAX), proliferating cell nuclear antigen (PCNA), cell proliferation marker protein (Ki67), caspase 3, the nuclear factor-κB (NFκB) and alfa smooth muscle actin (α-SMA). From this work, it is concluded that 1) renal damage is associated with lower expression level of SGLT causing disturbances in glycemic control even in the presence of DAPA 2) DAPA improved glycemic control in cases of diabetes mellitus. However, diabetic nephropathic rats were more hyperglycemic even in the presence of DAPA 3) DAPA showed renal protective effect as revealed by improved renal pathology, renal biochemical markers and lower expression levels of cell stress, apoptosis, regeneration and fibrosis markers 4) the tissue protective effect of DAPA is specific to kidneys as DAPA administration. Based on these results, care must be taken during DAPA administration in renal damage. Further studies are needed to investigate the nephroprotective effect of DAPA and its potential application in diabetic nephropathic patients DAPA significantly decreased the renal pathological lesions. The major recorded pathological lesion includes cellular infiltration, perivascular, periglumerular fibrosis, tubular cystic dilatation, luminar cast, glomerular lesions and hemorrhages. All these lesions were improved in DAPA treated groups. In DAPA treated groups there was lower expression level of apoptosis regulation protein (BAX), proliferating cell nuclear antigen (PCNA), cell proliferation marker protein (Ki67), caspase 3, the nuclear factor-κB (NFκB) and alfa smooth muscle actin (α-SMA). From this work, it is concluded that 1) renal damage is associated with lower expression level of SGLT causing disturbances in glycemic control even in the presence of DAPA 2) DAPA improved glycemic control in cases of diabetes mellitus. However, diabetic nephropathic rats were more hyperglycemic even in the presence of DAPA 3) DAPA showed renal protective effect as revealed by improved renal pathology, renal biochemical markers and lower expression levels of cell stress, apoptosis, regeneration and fibrosis markers 4) the tissue protective effect of DAPA is specific to kidneys as DAPA administration. Based on these results, care must be taken during DAPA administration in renal damage. Further studies are needed to investigate the nephroprotective effect of DAPA and its potential application in diabetic nephropathic patients