Inflammatory Bowel Disease (IBD) is associated with both impaired intestinal blood flow and increased risk of cardiovascular disease, but the functional role of perivascular nerves that control vasomotor function of mesenteric arteries (MAs) perfusing the intestine during IBD is unknown. Because perivascular sensory nerves and their transmitters calcitonin gene-related peptide (CGRP) and substance P (SP) are important mediators of both vasodilation and inflammatory responses, our objective was to identify IBD-related deficits in perivascular sensory nerve function and vascular neurotransmitter signaling. In MAs from an IL-10-/- mouse model, IBD significantly impairs electrical field stimulation (EFS)-mediated sensory vasodilation and inhibition of sympathetic vasoconstriction, despite decreased sympathetic nerve density and vasoconstriction. The MA content and EFS-mediated release of both CGRP and SP are decreased with IBD, but IBD has unique effects on each transmitter. CGRP nerve density, receptor expression, hyperpolarization and vasodilation are preserved with IBD. In contrast, SP nerve density and receptor expression are increased, and SP hyperpolarization and vasodilation are impaired with IBD. A key finding is that blockade of SP receptors restores EFS-mediated sensory vasodilation and enhanced CGRP-mediated vasodilation in MAs from IBD but not Control mice. Together, these data suggest that an aberrant role for the perivascular sensory neurotransmitter SP and its downstream signaling in MAs underlies vascular dysfunction with IBD. We propose that with IBD, SP signaling impedes CGRP-mediated sensory vasodilation, contributing to impaired blood flow. Thus, substance P and NK1 receptors may represent an important target for treating vascular dysfunction in IBD.

The percentage of the U.S. population over 65 is rapidly increasing, as is the incidence of chronic kidney disease (CKD). The kidney is susceptible to age-dependent alterations in structure, specifically tubulointerstitial fibrosis that leads to CKD. Matrix metalloproteinases (MMPs) were initially characterized as extracellular matrix (ECM) proteinases; however, it is clear that their biological role is much larger. We have observed increased gene expression of several MMPs in the aging kidney, including MMP-7. MMP-7 overexpression was observed starting at 16 months, with over a 500-fold upregulation in 2-year-old animals. Overexpression of MMP-7 is not observed in age-matched, calorically restricted controls that do not develop fibrosis and renal dysfunction, suggesting a role in the pathogenesis. In order to delineate the contributions of MMP-7 to renal dysfunction, we overexpressed MMP-7 in NRK-52E cells. High-throughput sequencing of the cells revealed that two collagen genes, Col1a2 and Col3a1, were elevated in the MMP-7 overexpressing cells. These two collagen genes were also elevated in aging rat kidneys and temporally correlated with increased MMP-7 expression. Addition of exogenous MMP-7, or conditioned media from MMP-7 overexpressing cells also increased Col1A2 expression. Inhibition of protein kinase A (PKA), src, and MAPK signaling at p38 and ERK was able to attenuate the MMP-7 upregulation of Col1a2. Consistent with this finding, increased phosphorylation of PKA, src, and ERK was seen in MMP-7 overexpressing cells and upon exogenous MMP-7 treatment of NRK-52E cells. These data suggest a novel mechanism by which MMP-7 contributes to the development of fibrosis leading to CKD.

Chronic kidney disease (CKD) is a significant public health problem as risk factors such as advanced age, obesity, hypertension and diabetes rise in the global population. Currently there are no effective pharmacologic treatments for this disease. The role of diet is important for slowing the progression of CKD and managing symptoms in later stages of renal insufficiency. While low protein diets are generally recommended, maintaining adequate levels of intake is critical for health. There is an increasing appreciation that the source of protein may also be important. Soybean protein has been the most extensively studied plant-based protein in subjects with kidney disease and has demonstrated renal protective properties in a number of clinical studies. Soy protein consumption has been shown to slow the decline in estimated glomerular filtration rate and significantly improve proteinuria in diabetic and non-diabetic patients with nephropathy. Soy's beneficial effects on renal function may also result from its impact on certain physiological risk factors for CKD such as dyslipidemia, hypertension and hyperglycemia. Soy intake is also associated with improvements in antioxidant status and systemic inflammation in early and late stage CKD patients. Studies conducted in animal models have helped to identify the underlying molecular mechanisms that may play a role in the positive effects of soy protein on renal parameters in polycystic kidney disease, metabolically-induced kidney dysfunction and age-associated progressive nephropathy. Despite the established relationship between soy and renoprotection, further studies are needed for a clear understanding of the role of the cellular and molecular target(s) of soy protein in maintaining renal function.

Cisplatin is one of the most potent and widely used antitumor drugs. However, the use of cisplatin is limited by its side effect, nephrotoxicity. Evidence has shown an increased incidence and severity of acute kidney injury (AKI) in the elderly. Previous studies from our laboratory demonstrate a decrease in α(E)-catenin expression in aged kidney. In this study, we investigated whether the loss of α(E)-catenin may increase cisplatin nephrotoxicity. To study the effects of reduced α(E)-catenin, a cell line with stable knockdown of α(E)-catenin (C2 cells) was used; NT3 is nontargeted control. C2 cells exhibited a significant loss of viability as determined by MTT assay compared with NT3 cells after cisplatin challenge, but showed no difference in lactate dehydrogenase (LDH) leakage. Increased caspase 3/7 activation and PARP cleavage was observed in C2 cells after cisplatin treatment. Z-VAD, a pan-caspase inhibitor, abolished the difference in susceptibility between NT3 and C2 cells. Interestingly, the expression of α(E)-catenin was further decreased after cisplatin treatment. Furthermore, in vivo data demonstrated a significant increase in serum creatinine at 72 h after a single dose of cisplatin in 24-month-old rats, but not in 4-month-old rats. Increased expression of KIM-1 and in situ apoptosis were also detected in aged kidney after cisplatin challenge. Taken together, these data suggest that loss of α(E)-catenin increases apoptosis of tubular epithelial cells which may contribute to the increased nephrotoxicity induced by cisplatin in aged kidney.

The aging kidney has a decreased ability to repair following acute kidney injury. Previous studies from our laboratory have demonstrated a loss in α‐catenin expression in the aging rat kidney. We hypothesize that loss of α‐catenin expression in tubular epithelial cells may induce changes that result in a decreased repair capacity. In these studies, we demonstrate that decreased α‐catenin protein expression is detectable as early as 20 months of age in male Fischer 344 rats. Protein loss is also observed in aged nonhuman primate kidneys, suggesting that this is not a species‐specific response. In an effort to elucidate alterations due to the loss of α‐catenin, we generated NRK‐52E cell lines with stable knockdown of α(E)‐catenin (C2 cells). Interestingly, C2 cells had decreased expression of N‐cadherin, decreased cell–cell adhesion, and increased monolayer permeability. C2 had deficits in wound repair, due to alterations in cell migration. Analysis of gene expression in the migrating control cells indicated that expression of N‐cadherin and N‐CAM was increased during repair. In migrating C2 cells, expression of N‐CAM was also increased, but the expression of N‐cadherin was not upregulated. Importantly, a blocking antibody against N‐cadherin inhibited repair in NRK‐52E cells, suggesting an important role in repair. Taken together, these data suggest that loss of α‐catenin, and the subsequent downregulation of N‐cadherin expression, is a mechanism underlying the decreased migration of tubular epithelial cells that contributes to the inability of the aging kidney to repair following injury.