The pathological hallmark of Parkinson’s disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn). Although PD is associated with these distinct histological changes, other pathological features such as microvascular alterations have been linked to neurodegeneration. These changes need to be investigated as they create a hostile brain microenvironment and may contribute to the development and progression of the disease. We use a human α-syn overexpression mouse model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human α-syn, impaired striatal dopamine fiber density, and an age-dependent motor deficit consistent with an impaired dopamine release. We demonstrate for the first time in this model a compromised blood–brain barrier integrity and dynamic changes in vessel morphology from angiogenesis at earlier stages to vascular regression at later stages. The vascular alterations are accompanied by a pathological activation of pericytes already at an early stage without changing overall pericyte density. Our data support and further extend the occurrence of vascular pathology as an important pathophysiological aspect in PD. The model used provides a powerful tool to investigate disease-modifying factors in PD in a temporal sequence that might guide the development of new treatments.

Increased senescent cell burden and dysregulation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We investigated whether senescence and NRF2 pathways may serve as drivers of uremia-induced VC using three complementary approaches: a novel model of induced VC in 5/6-nephrectomized rats supplemented with high phosphate and vitamin D; epigastric arteries from CKD patients with established medial calcification; and vascular smooth muscle cells (VSMCs) incubated with uremic serum. Expression of p16Ink4a and p21Cip1, as well as γ-H2A-positive cells, confirmed increased senescent cell burden at the site of calcium deposits in aortic sections in rats, and was similarly observed in calcified epigastric arteries from CKD patients through increased p16Ink4a expression. However, uremic serum-induced VSMC calcification was not accompanied by senescence. Expression of NRF2 and downstream genes, Nqo1 and Sod1, was associated with calcification in uremic rats, while no difference was observed between calcified and non-calcified EAs. Conversely, in vitro uremic serum-driven VC was associated with depleted NRF2 expression. Together, our data strengthen the importance of senescence and NRF2 pathways as potential therapeutic options to combat VC in CKD.

Vascular calcification is a risk factor for cardiovascular and kidney diseases. Medial calcification may differently affect the arterial tree depending on vessel location and smooth muscle injury. The aim was to map the anatomical distribution of vascular calcifications on different arteries and artery locations, in cultured artery rings (ex vivo) and in a rat model of elastocalcinosis (in vivo). Vascular calcification was assessed histologically (von Kossa staining of the media) and by calcium content measurement. Arteries of different sizes were harvested from untreated rats for ring culture and from the vitamin D3-nicotine (VDN) rat model for direct observation. When cultured in pro-calcifying conditions, thoracic aorta exhibited similar calcification from the arch to the diaphragm. Calcification increased in abdominal aorta along with the reduction in cross sectional area. Carotid and renal arteries exhibited similar ex vivo calcification. In VDN rats, calcification was greater in carotid artery than in aorta, and was accompanied by fibrosis and apoptosis. Ex vivo, calcification was increased by the induction of lesions on arteries. Along the vascular tree, calcification of the arterial wall increases with the narrowing of vessels in ex vivo ring culture and in vivo. The observed differences represent local susceptibility of the vessels to the calcifying processes.

BACKGROUND AND AIMS Obesity is an important risk factor for chronic kidney disease (CKD). It carries hemodynamic and morphologic changes in the kidney resulting in renal function reduction. CKD is associated with glomerulosclerosis and tubulointerstitial fibrosis that involve collagen deposition. The aim of the study was to evaluate the impact of obesity on kidney fibrosis in a model of 5/6th nephrectomized rats fed a cafeteria diet. METHOD Twenty four rats were fed acafeteria diet and 10 rats received a standard diet for 6 months. For each diet group, half of the rats underwent 5/6 nephrectomy (SNx) at 4 months. Expression of collagen type 1, 3, 4 was quantified by immunohistochemistry in kidney sections at 6 months. Adipocyte size was measured in epididymal adipose tissue (eWAT), and the presence of macrophages was determined by CD68 immunostaining. RESULTS Rats fed the cafeteria diet were hyperglycemic and hypertensive. Their body weight was higher than those fed the standard diet. SNx rats had increased serum creatinine levels, which were even higher in the cafeteria group (71 ± 10 µM) compared with standard diet group (54 ± 5 µM) (P < 0.05). Serum creatinine level was comparable in non-nephrectomized animals fed the cafeteria (32 ± 1 µM) or standard diet (29 ± 1 µM). Collagen 1 level in kidney tissue was increased in both SNx groups with no clear effect of the diet (respectively, 7.1 ± 0.6% and 8.9 ± 0.9% of tissue area with the standard and cafeteria diets). Renal expression of collagen 3 and 4 was significantly increased in SNx animals with cafeteria diet (8.6 ± 1.5 and 10.9 ± 1.9% tissue area, respectively) compared with control rats fed the same diet (5.2 ± 0.5 and 6.3 ± 0.6% tissue area, respectively). Adipocyte size of eWAT was significantly increased by cafeteria diet but reduced in nephrectomized rats. In the cafeteria-SNx group, CD68 immunostaining showed a significant increase in macrophage number in kidney (P = 0.01) and a consistent tendency in eWAT (Fig. 1). CONCLUSION Cafeteria diet-induced obesity worsened the 5/6 nephrectomy-induced CKD. The expression of collagens 3 and 4 as well as the number of macrophages were increased in kidneys from the cafeteria SNx group suggesting an exacerbation by pre-existing obesity of CKD-induced renal inflammation and fibrosis.