SGLT2 inhibition: a novel prospective strategy in treatment of diabetes mellitus.

The role of the kidney in glucose homeostasis and the potential of the kidney as a therapeutic target in type 2 diabetes is little appreciated. Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose re-absorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications, thus representing an innovative therapeutic strategy for the treatment of hyperglycemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. Sodium glucose co-transporter 2 (SGLT2) has a key role in re-absorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes.

Perspective in chronic kidney disease: targeting hypoxia-inducible factor (HIF) as potential therapeutic approach.

Tissue hypoxia is a pathologic feature of many human diseases like cancer, myocardial infarction, stroke, and kidney disease. Convincing data from clinical studies in patients with chronic renal failure point to chronic hypoxia of kidneys as the end result of multiple processes and mechanisms. In acute as well as chronic diseases, tissue hypoxia not only implies a risk of energy deprivation but also induces regulatory mechanisms with profound influence on gene expression. Moreover, once established, accumulating evidence points to this chronic hypoxia as the central player along with final common pathway to end-stage renal disease (ESRD). An evolutionarily preserved oxygen-sensing mechanism enables cells to adapt and maintain homeostasis under hypoxic conditions by transcriptional activation of a host of genes mediating metabolic adaptation, angiogenesis, energy conservation, erythropoiesis, in addition to cell survival. The endogenous oxygen-sensing mechanism incorporates hypoxia-inducible factors (HIFs) that hub cellular response to hypoxia and comprises a family of oxygen-sensitive basic helix-loop-helix proteins that control the cellular transcriptional response to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is thus a significant mediator of physiological responses to acute and chronic hypoxia. Since HIF is activated to suboptimal levels in pathogenic renal states, therapeutic activation holds a promising novel and effective approach to the treatment of ESRD. Current insights into the regulation of HIF may augment the understanding of the role of hypoxia in renal failure progression and may unbolt new options to improve hypoxia tolerance and induce nephroprotection.

Aqueous extract of Annona squamosa (L.) ameliorates renal failure induced by 5/6 nephrectomy in rat.

OBJECTIVE: To assess the renoprotective activity of the water extract of Annona squamosa in 5/6 nephrectomized animals. MATERIALS AND METHODS: For evaluating the renoprotective effects of Annona squamosa, 5/6 nephrectomized rats were used as a model for renal failure. The effects of hot-water extract of leaves of Annona squamosa L. (A. squamosa) at a dose 300 mg/kg bw on biochemical and urinary parameters like plasma urea, plasma creatinine, and urine creatinine were analyzed. For elucidating its effect on oxidative stress, renal superoxide dismutase (SOD) levels were measured. RESULTS: Nephrectomized rats (5/6) showed a significant rise in plasma urea and creatinine levels with a stable fall in urine creatinine. Treatment with A. squamosa extract (300 mg/kg bw) lead to a significant fall in the plasma urea and creatinine values with partial restoration to normal values along with a significant rise in the activity of SOD. CONCLUSION: Thus, therapeutic strategies against oxidative stress could be effective in renal diseases. This study provides an indication to investigate further the efficacy of A. squamosa as a novel agent for alleviating renal failure.

Hydroxyl radical mediates the augmented angiotensin II responses in thoracic aorta of spontaneously hypertensive rats.

AIM: To investigate the role of hydroxyl radical in augmented angiotensin II (Ang II) responses in the thoracic aorta of spontaneously hypertensive rats (SHR). METHODS: To elucidate the role of hydroxyl radical, we used edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) as a tool for our study. The vascular responses to Ang II (10(-10) to 10(-6) mol/l), tert-butyl hydroperoxide (tBHP; 10(-6) to 10(-2) mol/l) and H(2)O(2) (10(-6) to 10(-2) mol/l) were constructed in aortic preparations obtained from control (WKY) and SHR in the absence and presence of edaravone. RESULTS: The vascular responses to Ang II, tBHP and H(2)O(2) were found to be enhanced in aortic preparations from SHR as compared to control WKY rats. Edaravone selectively attenuated the augmented responses to Ang II but not to tBHP and H(2)O(2) suggesting that the .OH radical is involved in the augmented responses to Ang II. The elevated blood pressure in SHR was restored to a near normal value after 2 weeks of edaravone (10 mg kg(-1) i.p., b.i.d.) treatment. CONCLUSION: From the results we infer that hydroxyl radical stress augments Ang II responses in the thoracic aorta of SHR and, by attenuating these enhanced vascular responses, edaravone could serve as an adjuvant antioxidant therapy for the vascular complications of hypertension.