The Collecting Duct Is the Major Source of Prorenin in Diabetes

Abstract

Abstract-In addition to the juxtaglomerular apparatus, renin is also synthesized in renal tubular epithelium, including the collecting duct (CD). Angiotensin (Ang) II differentially regulates the synthesis of juxtaglomerular (inhibition) and CD (stimulation) renin. Because diabetes mellitus, a disease with high intrarenal renin-Ang system and Ang II activity, is characterized by high prorenin levels, we hypothesized that the CD is the major source of prorenin in diabetes. Renin granular content was visualized using in vivo multiphoton microscopy of the kidney in diabetic Munich-Wistar rats. Diabetes caused a 3.5-fold increase in CD renin, in contrast to less pronounced juxtaglomerular changes. Ang II type 1 receptor blockade with Olmesartan reduced CD renin to control levels but significantly increased juxtaglomerular renin. Using a fluorogenic renin assay, the prorenin component of CD renin content was measured by assessing the difference in enzymatic activity of medullary homogenates before and after trypsin activation of prorenin. Trypsinization caused no change in control renin activity but a 5-fold increase in diabetes. Studies on a CD cell line (M1) showed a 22-fold increase in renin activity after trypsinization and a further 35-fold increase with Ang II treatment. Therefore, prorenin significantly contributes to baseline CD renin. Diabetes, possibly via Ang II, greatly stimulates CD prorenin and causes hyperplasia of renin-producing connecting segments. These novel findings suggest that, in a rat model of diabetes, prorenin content and release from the CD may be more important than the juxtaglomerular apparatus in contrast to the existing paradigm. (Hypertension. 2008;51:1597-1604.)

Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation

“…4B). Consistent with this result, plasma renin measurements (27,28) revealed that Olfr78 −/− mice fed a standard chow diet rich in plant polysaccharides have significantly lower plasma renin levels than wild-type mice fed the same diet ( Fig. 4C, P < 0.05).…”

“…Propionate (P) induces quinacrine release (which is a surrogate for renin release) in wild-type but not Olfr78 −/− animals (B). PRA levels (plasma renin activity, normalized ex vivo to wild-type and determined as the slope of the time course of fluorescent product production in a kinetic assay) (27,28) are significantly reduced in Olfr78 −/− mice (C). * indicates statistical significance.…”

Diabetic complications: A role for the prorenin–(pro)renin receptor–TGF-β1 axis?

“…A recent study A c c e p t e d M a n u s c r i p t 6 suggests that the source of the elevated prorenin in diabetes mellitus is the collecting duct. Unexpectedly, at this site Ang II stimulates the synthesis of prorenin (Kang et al, 2008), as opposed to its inhibiting effects in the juxtaglomerular apparatus. Furthermore, plasma prorenin in diabetic subjects plasma was found to correlate with the renovascular response to captopril (Stankovic et al, 2006).…”

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

“…19,[46][47][48][49][50][51][52][53][54] Interestingly, mechanisms for regulating tubular renin seem to be independent of those in the JG cell. 47,48,50,52 Proximal tubular cells express mRNA [54][55][56] and protein 53,57 for ACE and Aogen. [58][59][60][61] In vivo evidence that proximal tubular cells may synthesize Ang II has also been reported.…”

“…The intrarenal RAAS is thought to be activated during diabetes, based on in vitro and in vivo evidence. 21,22,24,25,48,54,55,69,78 Therefore, the effect of renin inhibition in diabetic conditions is of great interest.…”