Open AccessActivation of the intrarenal renin‐angiotensin‐system in murine polycystic kidney disease
Author(s) -
Saigusa Takamitsu,
Dang Yujing,
Bunni Marlene A.,
Amria May Y.,
Steele Stacy L.,
Fitzgibbon Wayne R.,
Bell P. Darwin
Publication year - 2015
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12405
Subject(s) - cilium , kidney , polycystic kidney disease , endocrinology , renin–angiotensin system , medicine , angiotensin ii , pkd1 , biology , cholangiocyte , blood pressure , microbiology and biotechnology
Abstract The mechanism for early hypertension in polycystic kidney disease ( PKD ) has not been elucidated. One potential pathway that may contribute to the elevation in blood pressure in PKD is the activation of the intrarenal renin‐angiotensin‐system ( RAS ). For example, it has been shown that kidney cyst and cystic fluid contains renin, angiotensin II (Ang II ), and angiotensinogen (Agt). Numerous studies suggest that ciliary dysfunction plays an important role in PKD pathogenesis. However, it is unknown whether the primary cilium affects the intrarenal RAS in PKD . The purpose of this study was to determine whether loss of cilia or polycystin 1 ( PC 1) increases intrarenal RAS in mouse model of PKD . Adult Ift88 and Pkd1 conditional floxed allele mice with or without cre were administered tamoxifen to induce global knockout of the gene. Three months after tamoxifen injection, kidney tissues were examined by histology, immunofluorescence, western blot, and mRNA to assess intrarenal RAS components. SV 40 immortalized collecting duct cell lines from hypomorphic Ift 88 mouse were used to assess intrarenal RAS components in collecting duct cells. Mice without cilia and PC 1 demonstrated increased kidney cyst formation, systolic blood pressure, prorenin, and kidney and urinary angiotensinogen levels. Interestingly immunofluorescence study of the kidney revealed that the prorenin receptor was localized to the basolateral membrane of principal cells in cilia (−) but not in cilia (+) kidneys. Collecting duct cAMP responses to Ang II administration was greater in cilia (−) vs. cilia (+) cells indicating enhanced intrarenal RAS activity in the absence of cilia. These data suggest that in the absence of cilia or PC 1, there is an upregulation of intrarenal RAS components and activity, which may contribute to elevated blood pressure in PKD.