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Chronic kidney disease (CKD) poses a considerable medical and public health challenge, and the Dahl/Salt Sensitive (Dahl/SS) strain is often used for CKD study. Extracellular superoxide dismutase (SOD3) is important for removing extracellular superoxide anions and is highly expressed in renal tissue. Using a novel rat strain with loss-of-function mutation of SOD3 created by replacing glutamate 124 of SOD3 with aspartic acid (SOD3E124D rat strain), we determined the effect of SOD3 on renal function and blood pressure in Dahl/SS rats. We find that SOD3E124D rats are phenotypically indistinguishable from wild type rats through 8 weeks of age, but develop profound CKD characterized by focal necrosis and fibrosis, glomerulosclerosis, massive proteinaceous cast accumulation with tubular dilatation, interstitial fibrosis with hypertension and renal failure by 21 weeks. The SOD3E124D strain represents a unique rat model that spontaneously develops CKD in an age-dependent fashion. The finding that loss of SOD3 causes CKD indicates that extracellular oxidative stress contributes to CKD and renal failure. Image 1 • Superoxide dismutase 3 (SOD3) plays an important role in various diseases. • Chronic kidney disease (CKD) poses medical and public health challenge. • Loss-of-function mutation of SOD3 cause severe age-dependent CKD in rats. • A loss-of-function mutation of SOD3 cause severe systolic hypertension in rats. • The SOD3 mutation strain represents a unique rat CKD model. [ABSTRACT FROM AUTHOR]

Adenosine exerts numerous protective actions in the heart, including attenuation of cardiac hypertrophy. Adenosine kinase (ADK) converts adenosine to adenosine monophosphate (AMP) and is the major route of myocardial adenosine metabolism, however, the impact of ADK activity on cardiac structure and function is unknown. To examine the role of ADK in cardiac homeostasis and adaptation to stress, conditional cardiomyocyte specific ADK knockout mice (cADK−/−) were produced using the MerCreMer-lox-P system. Within 4 weeks of ADK disruption, cADK−/− mice developed spontaneous hypertrophy and increased β-Myosin Heavy Chain expression without observable LV dysfunction. In response to 6 weeks moderate left ventricular pressure overload (transverse aortic constriction;TAC), wild type mice (WT) exhibited ~60% increase in ventricular ADK expression and developed LV hypertrophy with preserved LV function. In contrast, cADK−/− mice exhibited significantly greater LV hypertrophy and cardiac stress marker expression (atrial natrurietic peptide and β-Myosin Heavy Chain), LV dilation, reduced LV ejection fraction and increased pulmonary congestion. ADK disruption did not decrease protein methylation, inhibit AMPK, or worsen fibrosis, but was associated with persistently elevated mTORC1 and p44/42 ERK MAP kinase signaling and a striking increase in microtubule (MT) stabilization/detyrosination. In neonatal cardiomyocytes exposed to hypertrophic stress, 2-chloroadenosine (CADO) or adenosine treatment suppressed MT detyrosination, which was reversed by ADK inhibition with iodotubercidin or ABT-702. Conversely, adenoviral over-expression of ADK augmented CADO destabilization of MTs and potentiated CADO attenuation of cardiomyocyte hypertrophy. Together, these findings indicate a novel adenosine receptor-independent role for ADK-mediated adenosine metabolism in cardiomyocyte microtubule dynamics and protection against maladaptive hypertrophy. [ABSTRACT FROM AUTHOR]