Changes in mean arterial pressure predict degranulation of renomedullary interstitial cells.

1. Renomedullary interstitial cells (RMIC) are characterized by numerous intracellular granules thought to contain renal medullary antihypertensive substances. However, the nature of the trigger for RMIC degranulation remains to be elucidated. The present study examines the effects of acute alterations in mean arterial pressure (MAP) and medullary blood flow (MBF) on RMIC granulation. 2. Basal MAP and MBF in anaesthetized Sprague-Dawley rats (n = 4/group) were altered by intravenous infusions of vasoactive agents, including angiotensin II alone or with a nitric oxide (NO) synthase inhibitor (N-omega-nitro-l-arginine) or NO donor (sodium nitroprusside), noradrenaline and by carotid artery clamping. Following these treatments, kidneys were examined by electron microscopy and the absolute volume of granules in the renal medulla was calculated using unbiased stereological methods. 3. Acute increases in MAP, regardless of the treatment causing the increase, were associated with a reduction in the absolute volume of granules in the range of 42-67%. Regression analysis revealed that only increases in MAP, but not MBF, strongly predict RMIC degranulation. 4. Despite previous reports that changes in MBF activate renomedullary antihypertensive activity, we conclude that the change in MAP is an important determinant of the activity of the blood pressure-lowering mechanism of the renal medulla, with the assumption that the medullary lipids mediate the antihypertensive property of the renal medulla.

Prevention of diabetes-induced albuminuria in transgenic rats overexpressing human aldose reductase.

Studies using pharmacologic inhibitors have implicated the enzyme aldose reductase in the pathogenesis of albuminuria and diabetic renal disease. However, a clear conclusion is not easily drawn from such studies since these pharmacologic inhibitors have nonspecific properties. To examine further the role of aldose reductase, we have overexpressed the human enzyme in a transgenic rat model. Transgene expression in the kidney was predominantly localized to the outer stripe of the outer medulla, compatible with the histotopography of the straight (S3) proximal tubule. The effect of enzyme overexpression on diabetes-induced renal function and structure was then investigated. Contrary to what may have been anticipated from the previous enzyme inhibition studies, diabetes-induced albuminuria was completely prevented by the overexpression of aldose reductase. No effect of overexpression of aldose reductase on renal structure nor on urinary excretion of beta2-microglobulin and N-acetyl-beta-D-glucosaminidase was observed in this transgenic rat model. In conclusion, our study strongly suggests that multiple roles for aldose reductase may give it a more complex place in diabetic nephropathy than is currently recognized.

Angiotensin II binding to renomedullary interstitial cells is regulated by osmolality.

Angiotensin II (Ang II) AT(1A) receptors are localized to renomedullary interstitial cells (RMIC) in the inner stripe of the outer medulla but not in the inner medulla. Thus, there seems to be a correlation between decreases in AT(1A) receptor binding to RMIC and increases in interstitial osmolality, suggesting that osmolality is important in determining Ang II binding to RMIC. Cultured RMIC were incubated in media of differing osmolalities (330, 630, 930, and 1230 mOsm/kg H(2)O). (125)I-[Sar(1), Ile(8)] Ang II binding to AT(1A) receptors on RMIC grown in hyperosmolal media (930 mOsm/kg H(2)O) was reduced compared with isoosmolal (330 mOsm/kg H(2)O) media and was progressively reduced with further increases of osmolality. Similar studies were performed using bradykinin (BK) as a control peptide. Binding of the BK receptor ligand (125)I-[HPP-Hoe 140] to B(2) receptors was not affected by varying osmolality of the media. Reverse transcriptase-PCR demonstrated the presence of the mRNA expression for both AT(1A) and B(2) receptors at each osmolality. The conclusion is that osmolality modulates Ang II binding to RMIC; in these cells, this phenomenon is restricted to Ang II as BK binding is not affected. Osmolality-induced changes in Ang II binding may modulate the actions of this peptide on RMIC and provide an important mechanism by which these cells modulate renal medullary function.