The Pathological Role of Pro(Renin) Receptor in Renal Inflammation.

(Pro)renin receptor (PRR) is the recently discovered component of the renin-angiotensin-aldosterone system (RAS). Many organs contain their own RAS, wherein PRR can exert organ-specific localized effects. The Binding of prorenin/renin to PRR activates angiotensin-dependent and independent pathways which leads to the development of physiological and pathological effects. Continued progress in PRR research suggests that the upregulation of PRR contributes to the development of hypertension, glomerular injury, and progression of kidney disease and inflammation. In the current review, we highlight the function of the PRR in renal inflammation in pathophysiological conditions.

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators.

Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.

(Pro)Renin receptor mediates obesity-induced antinatriuresis and elevated blood pressure via upregulation of the renal epithelial sodium channel.

Recent studies have demonstrated that the renal (pro)renin receptor (PRR) regulates expression of the alpha subunit of the epithelial sodium channel (α-ENaC). In this study we hypothesized that the renal PRR mediates high fat diet (HFD)-induced sodium retention and elevated systolic blood pressure (SBP) by enhancing expression of the epithelial sodium channel (α-ENaC). In our study we used a recently developed inducible nephron specific PRR knockout mouse. Mice (n = 6 each group) were allocated to receive regular diet (RD, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 10 weeks. Body weight (BW), SBP, urine volume (UV) and urine sodium (UNaV), as well as renal interstitial Angiotensin II (Ang II), and renal medullary expression of PRR, p-SGK-1, α-ENaC were monitored in RD and HFD mice with or without PRR knockout. At baseline, there were no significant differences in BW, BP, UV or UNaV between different animal groups. At the end of the study, HFD mice had significant increases in SBP, BW, and significant reductions in UV and UNaV. Compared to RD, HFD significantly increased mRNA and protein expression of PRR, α-ENaC, p-SGK-1, and Ang II. Compared to HFD alone, PRR knockout mice on HFD had reduced mRNA and protein expression of PRR, p-SGK-1, and α-ENaC, as well as increased UV, UNaV and significantly reduced SBP. RIF Ang II was significantly increased by HFD and did not change in response to PRR knockout. We conclude that obesity induced sodium retention and elevated SBP are mediated by the PRR-SGK-1- α-ENaC pathway independent of Ang II.

Liver-specific rescuing of CEACAM1 reverses endothelial and cardiovascular abnormalities in male mice with null deletion of Ceacam1 gene.

OBJECTIVE: Mice with global null mutation of Ceacam1 (Cc1-/-), display impairment of insulin clearance that causes hyperinsulinemia followed by insulin resistance, elevated hepatic de novo lipogenesis, and visceral obesity. In addition, they manifest abnormal vascular permeability and elevated blood pressure. Liver-specific rescuing of Ceacam1 reversed all of the metabolic abnormalities in Cc1-/-liver+ mice. The current study examined whether Cc1-/- male mice develop endothelial and cardiac dysfunction and whether this relates to the metabolic abnormalities caused by defective insulin extraction. METHODS AND RESULTS: Myography studies showed reduction of agonist-stimulated nitric oxide production in resistance arterioles in Cc1-/-, but not Cc1-/-liver+ mice. Liver-based rescuing of CEACAM1 also attenuated the abnormal endothelial adhesiveness to circulating leukocytes in parallel to reducing plasma endothelin-1 and recovering plasma nitric oxide levels. Echocardiography studies revealed increased septal wall thickness, cardiac hypertrophy and reduced cardiac performance in Cc1-/-, but not Cc1-/-xliver+ mice. Insulin signaling experiments indicated compromised IRS1/Akt/eNOS pathway leading to lower nitric oxide level, and activated Shc/MAPK pathway leading to more endothelin-1 production in the aortae and hearts of Cc1-/-, but not Cc1-/-xliver+ mice. The increase in the ratio of endothelin-1 receptor A/B indicated an imbalance in the vasomotor activity of Cc1-/- mice, which was normalized in Cc1-/-xliver+ mice. CONCLUSIONS: The data underscore a critical role for impaired CEACAM1-dependent hepatic insulin clearance pathways and resulting hyperinsulinemia and lipid accumulation in aortae and heart in regulating the cardiovascular function.

Prorenin receptor mediates inflammation in renal ischemia.

We hypothesized that PRR contributes to renal inflammation in the 2-kidney, 1-clip (2K1C) renal ischaemia model. Male Sprague-Dawley rats were fed normal sodium diet. Blood pressure (BP) was obtained on days 0 and 28 after left renal artery clipping that reduced renal blood flow by 40%. Renal expression of TNF-α, COX-2, NF-κB, IL-1ß, MCP-1 and collagen type I were assessed in sham and 2K1C rats with or without left renal administration of scramble or PRR shRNA. At baseline, there were no differences in BP. Compared to sham, MAP significantly increased in clipped animals (sham 102 ± 1.9 vs 2K1C 131.8 ± 3.09 mmHg, P < .05) and was not influenced by scramble or PRR shRNA treatment. Compared to sham and contra lateral (non-clipped) kidney, there was upregulation in mRNA and protein expression of PRR (99% and 45%, P < .01), TNF-α (72% and 50%, P < .05), COX-2 (72% and 39%, P < .05), p-NF-κB (92%, P < .05), MCP-1 (87%, P < .05) and immunostaining of collagen type I in the clipped kidney. These increases were not influenced by scramble shRNA. Compared to 2K1C and scramble shRNA, PRR shRNA treatment in the clipped kidney significantly reduced the expression of PRR (62% and 57%, P < .01), TNF-α (51% and 50%, P < .05), COX-2 (50% and 56%, P < .05), p-NF-κB by 68% (P < .05), MCP-1 by 73% (P < .05) and collagen type I respectively. Ang II was increased in both kidneys and did not change in response to scramble or PRR shRNA treatments. We conclude that PRR mediates renal inflammation in renal ischaemia independent of blood pressure and Ang II.

Interaction of the renin angiotensin and cox systems in the kidney.

Cyclooxygenase-2 (COX-2) plays an important role in mediating actions of the renin-angiotensin system (RAS). This review sheds light on the recent developments regarding the complex interactions between components of RAS and COX-2; and their implications on renal function and disease. COX-2 is believed to counter regulate the effects of RAS activation and therefore counter balance the vasoconstriction effect of Ang II. In kidney, under normal conditions, these systems are essential for maintaining a balance between vasodilation and vasoconstriction. However, recent studies suggested a pivotal role for this interplay in pathology. COX-2 increases the renin release and Ang II formation leading to increase in blood pressure. COX-2 is also associated with diabetic nephropathy, where its upregulation in the kidney contributes to glomerular injury and albuminuria. Selective inhibition of COX-2 retards the progression of renal injury. COX-2 also mediates the pathologic effects of the (Pro)renin receptor (PRR) in the kidney. In summary, this review discusses the interaction between the RAS and COX-2 in health and disease.