Introduction. Transgenic rats with inducible angiotensin II (Ang II)-dependent hypertension (strain name: TGR[Cyp1a1-Ren2]) were generated by inserting the mouse Ren2 renin gene, fused to the cytochrome P450 1a1 (Cyp1a1) promoter, into the genome of the rat. The present study was performed to characterise the changes in plasma and kidney tissue Ang II levels and in renal haemodynamic function in Cyp1a1-Ren2 rats following induction of either slowly developing or malignant hypertension in these transgenic rats. Materials and Methods. Arterial blood pressure (BP) and renal haemodynamics and excretory function were measured in pentobarbital sodium-anaesthetised Cyp1a1-Ren2 rats fed a normal diet containing either a low dose (0.15%, w/w for 14-15 days) or high dose (0.3%, w/w for 11-12 days) of the aryl hydrocarbon indole-3-carbinol (I3C) to induce slowly developing and malignant hypertension, respectively. In parallel experiments, arterial blood samples and kidneys were harvested for measurement of Ang II levels by radioimmunoassay. Results. Dietary I3C increased plasma renin activity (PRA), plasma Ang II levels, and arterial BP in a dose-dependent manner. Induction of different fixed levels of renin gene expression and PRA produced hypertensive phenotypes of varying severity with rats developing either mild or malignant forms of hypertensive disease. Administration of I3C, at a dose of 0.15% (w/w), induced a slowly developing form of hypertension whereas administration of a higher dose (0.3%) induced a more rapidly developing hypertension and the clinical manifestations of malignant hypertension including severe weight loss. Both hypertensive phenotypes were characterised by reduced renal plasma flow, increased filtration fraction, elevated PRA, and increased plasma and intrarenal Ang II levels. These I3C-induced changes in renal haemodynamics, PRA and kidney Ang II levels were more pronounced in Cyp1a1-Ren2 rats with malignant hypertension. Chronic administration of the AT 1 -receptor antagonist,

Ketoacidosis is a rare but serious side effect of SGLT2 inhibitors. It is being increasingly reported as these drugs are now commonly being prescribed in the primary care setting. Awareness that DKA can occur in the setting of relative euglycemia is critical to recognize this life-threatening complication of diabetes. More research is needed to better understand the underlying pathophysiology and precipitating factors leading to ketoacidosis in SGLT-2 inhibitor treated patients.

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