Renal cyst growth is the main determinant for hypertension and concentrating deficit in Pkd1 -deficient mice

Abstract

We have bred a Pkd1 floxed allele with a nestin-Cre expressing line to generate cystic mice with preserved GFR to address the pathogenesis of complex ADPKD phenotypes. Hypertension affects about 60% of these patients before loss of renal function, leading to significant morbimortality. Cystic mice were hypertensive at 5 and 13 weeks of age, a phenotype not seen in non-cystic controls and Pkd1-haploinsufficient animals, which do not develop renal cysts. Fractional sodium excretion was reduced in cystic mice at these ages. Angiotensinogen gene expression was higher in cystic than non-cystic kidneys at 18 weeks, while ACE and the AT1 receptor were expressed in renal cyst epithelia. Cystic animals displayed increased renal cAMP, cell proliferation and apoptosis. At 24 weeks mean arterial pressure and fractional sodium excretion did not significantly differ between the cystic and non-cystic groups, whereas cardiac mass increased in cystic mice. Renal concentrating deficit is also an early finding in ADPKD. Maximum urine osmolality and urine nitrite excretion were reduced in 10–13 and 24-week-old cystic mice, deficits not found in haploinsufficient and non-cystic controls. A trend of higher plasma vasopressin was observed in cystic mice. Thus, cyst growth most probably plays a central role in early-stage ADPKD-associated hypertension, with activation of the intrarenal renin-angiotensin system as a key mechanism. Cyst expansion is also likely essential for the development of the concentrating deficit in this disease. Our findings are consistent with areas of reduced perfusion in the kidneys of patients with ADPKD.

Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout

“…HTG+ animals were shown not to have increased mean arterial pressure (MAP) at 13 wk in the 129Sv background (14) and our current study has confirmed this finding in the C57BL/6 background (Table S4). On the other hand, we have previously shown that CYG+ mice presented elevated MAP at 5 and 13 wk in the C57BL/6 background (14), while a non-significant higher numerical value was observed at 24 wk (Table S4).…”

“…Homozygous mice for a Pkd1- floxed allele, in turn, with a mosaic pattern of gene inactivation driven by a Nestin-Cre transgene and excision of exons 2–4 ( Pkd1 cond/cond : Nestin cre ; CYG+) (14, 17), developed a milder renal phenotype in our animal-care facility than in another center (14, 19). The CYG+ mice develop cystic kidneys and increased mean arterial pressure (MAP) (14), reproducing the ADPKD phenotype, however do not have a systemic Pkd1 -haploinsufficiency background. Noncystic animals ( Pkd1 cond/cond ; NC) were their controls.…”

“…Critical points relating Pkd1 / Pkd2 deficiency, including human ADPKD, and cardiac function and structure, therefore, remain to be elucidated. To address this concept, we sought to analyze the cardiac phenotype in three mouse models with distinct profiles of Pkd1 -deficiency: noncystic Pkd1 -haplonsufficient (14, 17–18), cystic Pkd1 cond/cond : Nestin cre (14, 19) and severely cystic Pkd1 V/V mice (20). …”

Flow regulation of endothelin-1 production in the inner medullary collecting duct

“…The cause for this early hypertension has been related to cyst compression of normal renal structures and activation of the intrarenal renin-angiotensin system (33). However, a recent study (9) found that hypertension was present in a mouse model of Pkd1 deficiency when only minimal renal cysts were present. Notably, while renal ET-1 production is increased in cystic kidney disease after significant renal damage has occurred, there is no information on renal or CD ET-1 production in kidneys without functional polycystin-2 but before cysts form.…”

Bases moleculares e celulares das nefropatias hereditárias císticas

“…Nesse contexto, destacam-se os efeitos da hipertensão arterial sistêmica (HAS), presente em cerca de 60% dos pacientes com DRPAD antes mesmo de prejuízos na função renal serem detectados 13,14 e 10 anos antes que na população geral 15 . A gênese da HAS ainda não está completamente elucidada na DRPAD, porém a ativação do sistema renina-angiotensina-aldosterona (SRAA) em resposta à compressão vascular decorrente da distensão dos cistos parece cumprir um papel central na determinação desse fenótipo 16 . O desenvolvimento de hipertrofia ventricular esquerda e de miocardiopatia dilatada idiopática também impactam no prognóstico da doença 17,18 .…”