The role of vasoactive peptides in skin homeostasis-focus on adiponectin and the kallikrein-kinin system.

Vasoactive peptides often serve a multitude of functions aside from their direct effects on vasodynamics. This article will review the existing literature on two vasoactive peptides and their involvement in skin homeostasis: adiponectin and-as the main representative of the kallikrein-kinin system-bradykinin. Adiponectin is the most abundantly expressed adipokine in the human organism, where it is mainly localized in fat depots including subcutaneous adipose tissue, from where adiponectin can exert paracrine effects. The involvement of adiponectin in skin homeostasis is supported by a number of studies reporting the effects of adiponectin in isolated human keratinocytes, sebocytes, fibroblasts, melanocytes, and immune cells. Regarding skin pathology, the potential involvement of adiponectin in psoriasis, atopic dermatitis, scleroderma, keloid, and melanogenesis is discussed in this article. The kallikrein-kinin system is composed of a variety of enzymes and peptides, most of which have been identified to be expressed in the skin. This also includes the expression of bradykinin receptors on most skin cells. Bradykinin is one of the very few hormones that is targeted by treatment in routine clinical use in dermatology-in this case for the treatment of hereditary angioedema. The potential involvement of bradykinin in wound healing, psoriasis, and melanoma is further discussed in this article. This review concludes with a call for additional preclinical and clinical studies to further explore the therapeutic potential of adiponectin supplementation (for psoriasis, atopic dermatitis, wound healing, scleroderma, and keloid) or pharmacological interference with the kallikrein-kinin system (for wound healing, psoriasis, and melanoma).

Protective effect of sacubitril/valsartan (Entresto) on kidney function and filtration barrier injury in a porcine model of partial nephrectomy.

Kidney surgery often includes organ ischaemia with a risk of acute kidney injury. The present study tested if treatment with the combined angiotensin II-angiotensin II receptor type 1 and neprilysin blocker Entresto (LCZ696, sacubitril/valsartan) protects filtration barrier and kidney function after ischaemia and partial nephrectomy (PN) in pigs. Single kidney glomerular filtration rate (GFR) by technetium-99m diethylene-triamine-pentaacetate clearance was validated (n = 6). Next, four groups of pigs were followed for 15 days (n = 24) after PN (one-third right kidney, 60 min ischaemia) + Entresto (49/51 mg/day; n = 8), PN + vehicle (n = 8), sham + Entresto (49/51 mg/day; n = 4) and sham + vehicle (n = 4). GFR, diuresis and urinary albumin were measured at baseline and from each kidney after 15 days. The sum of single-kidney GFR (right 25 ± 6 mL/min, left 31 ± 7 mL/min) accounted for the total GFR (56 ± 14 mL/min). Entresto had no effect on baseline blood pressure, p-creatinine, mid-regional pro-atrial natriuretic peptide (MR-proANP), heart rate and diuresis. After 15 days, Entresto increased GFR in the uninjured kidney (+23 ± 6 mL/min, P < .05) and reduced albuminuria from both kidneys. In the sham group, plasma MR-proANP was not altered by Entresto; it increased to similar levels 2 h after surgery with and without Entresto. Fractional sodium excretion increased with Entresto. Kidney histology and kidney injury molecule-1 in cortex tissue were not different. In conclusion, Entresto protects the filtration barrier and increases the functional adaptive response of the uninjured kidney.

Protection of kidney function and tissue integrity by pharmacologic use of natriuretic peptides and neprilysin inhibitors.

With variable potencies atrial-, brain-type and c-type natriuretic peptides (NP)s, best documented for ANP and its analogues, promote sodium and water excretion, renal blood flow, lipolysis, lower blood pressure, and suppress renin and aldosterone secretion through interaction predominantly with cGMP-coupled NPR-A receptor. Infusion of especially ANP and its analogues up to 50 ng/kg/min in patients with high risk of acute kidney injury (cardiac vascular bypass surgery, intraabdominal surgery, direct kidney surgery) protects kidney function (GFR, plasma flow, medullary flow, albuminuria, renal replacement therapy, tissue injury) at short term and also long term and likely additively with the diuretic furosemide. This documents a pharmacologic potential for the pathway. Neprilysin (NEP, neutral endopeptidase) degrades NPs, in particular ANP, and angiotensin II. The drug LCZ696, a mixture of the neprilysin inhibitor sacubitril and the ANGII-AT1 receptor blocker valsartan, was FDA approved in 2015 and marketed as Entresto®. In preclinical studies of kidney injury, LCZ696 and NPs lowered plasma creatinine, countered hypoxia and oxidative stress, suppressed proinflammatory cytokines, and inhibited fibrosis. Few randomized clinical studies exist and were designed with primary cardiac outcomes. The studies showed that LCZ696/entresto stabilized and improved glomerular filtration rate in patients with chronic kidney disease. LCZ696 is safe to use concerning kidney function and stabilizes or increases GFR. In perspective, combined AT1 and neprilysin inhibition is a promising approach for long-term renal protection in addition to AT1 receptor blockers in acute kidney injury and chronic kidney disease.

The role of the renin-angiotensin system in skin physiology and pathophysiology.

Since its first description around the year 2000, the local renin-angiotensin system (RAS) in skin has been subject of an increasing number of studies with many additions over the last two to three years. A focus of research has been investigations on the role of cutaneous angiotensin receptors and locally synthesised angiotensin II in wound healing, in dermatoses associated with skin fibrosis and in melanoma. This review will provide an introduction into the RAS with emphasis on information relevant for the cutaneous RAS. It will discuss the role of the RAS in skin physiology, followed by a detailed review of the existing literature addressing the role of local angiotensin II and angiotensin AT1 and AT2 receptors in wound healing and in various skin diseases such as hypertrophic scars/keloids, scleroderma, dystrophic epidermolysis bullosa, Dupuytren's disease, squamous cell carcinoma, melanoma and psoriasis. In a final section, the potential relevance of drugs, which interfere with the RAS, for future therapy of dermatological disorders is discussed. Collectively, research about the RAS in skin can currently be described as an area, which has gained increasing attention by basic researchers, thus resulting in a multitude of preclinical studies pointing to the potential relevance of components of the RAS as drug targets in dermatological diseases. With a few small clinical studies already performed successfully for indications such as hypertrophic scars and keloids, it can be said that the skin RAS is now in the critical phase of translation from preclinical evidence to clinical use.