Biomedical subjects

Jean-Jacques Boffa

Publications and source records attributed to Jean-Jacques Boffa.

9 recordsLinked to original sources

PubMed2006

Acute renal failure associated with immune restoration inflammatory syndrome.

BACKGROUND: A 30-year-old HIV-infected woman presented with fever and abdominal pain 4 days after initiation of highly active antiretroviral therapy (HAART), and 1 month after initiation of antimicrobial therapy for Mycobacterium tuberculosis infection. A diagnosis of immune restoration inflammatory syndrome (IRIS) was considered, and corticosteroids were started. Steroid therapy doses were progressively tapered, during which time the patient developed renal failure with enlarged kidneys. A renal biopsy showed acute interstitial nephritis. Extensive investigations failed to detect active infection. The efficacy of HAART was attested by increased CD4+ cell counts and undetectable viral replication. INVESTIGATIONS: Physical examination, plasma viral load and CD4+ cell count, abdominal and renal ultrasound, renal and peritoneal biopsies, renal and liver function, chest X-ray, and bronchoalveolar lavage culture. DIAGNOSIS: Acute renal failure secondary to IRIS. MANAGEMENT: Prednisone therapy.

Acute Kidney Injury↗

PubMed2005

Reversal of renal lesions following interruption of nitric oxide synthesis inhibition in transgenic mice.

BACKGROUND: Renal fibrosis, a common complication of hypertension and diabetes is considered as a non-curable disease and is characterized by the abnormal accumulation of collagen I within the kidney. Chronic inhibition of nitric oxide (NO) synthesis is a model of hypertension associated with the development of nephroangiosclerosis. The present study investigated whether halt of NO inhibition leads to the regression of renal sclerotic lesions. METHODS: The NO deficiency (N(G)-nitro-L-arginine methylester; L-NAME) model of hypertension was applied in transgenic mice harbouring the luciferase reporter gene under the control of the collagen I-alpha2 chain promoter. RESULTS: Systolic pressure gradually increased following the administration of L-NAME, and reached 160 mmHg after 8-10 weeks. Activation of collagen I gene within the renal vasculature preceded the blood pressure increase and was accompanied by the appearance of sclerotic glomeruli and tubulointerstitial infiltration. After renal lesions had been established (20 weeks), animals were divided in three subgroups for an additional experimental period of 10 weeks: first group continued to receive L-NAME, in the second, L-NAME administration was stopped to allow endogenous NO synthesis and in the third the removal of L-NAME was combined with endothelin receptor antagonism. Removal of L-NAME decreased, without normalizing, systolic pressure and collagen I gene activity; renal morphology was substantially improved, and tubulointerstitial infiltration disappeared. Combination of L-NAME removal with endothelin antagonism normalized collagen I gene expression and further improved renal morphology without further decreasing blood pressure. CONCLUSION: Manipulating the balance between NO/vasoconstrictors in favour of NO could provide a curative approach against renal inflammatory and fibrotic complications associated to hypertension.

Animals↗

PubMed2004

Maintenance of renal vascular reactivity contributes to acute renal failure during endotoxemic shock.

Septic shock is characterized by hypotension and decreased systemic vascular resistance and impaired vascular reactivity. Renal vasoconstriction markedly contrasts with sepsis-induced generalized systemic vasodilation, which is strongly dependent on nitric oxide. Whether maintained renal vascular reactivity to vasoconstrictors contributes to the decrease in renal blood flow (RBF) and GFR observed during LPS-induced sepsis was tested by assessment of the acute effects of pressor agents on mean arterial pressure (MAP) and renal hemodynamics in endotoxemic and control mice. LPS-injected mice displayed lower MAP, RBF, and GFR than controls (P < 0.001). Despite a lower MAP, basal renal vascular resistance (RVR) was higher during endotoxemia (P < 0.02). Angiotensin II infusion produced a weaker MAP response in septic mice (24 versus 37%; P < 0.005), suggesting impaired vasoconstriction and hyporeactivity. A similar MAP increase was observed between groups during norepinephrine (NE) infusion. The MAP increase to nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME) was much greater in LPS-treated mice (41 versus 15%, P = 0.01), indicating a strong influence of nitric oxide in sepsis. In contrast, the RBF and RVR responses to angiotensin II, NE, or L-NAME were similar in both groups. Moreover, vasopressin produced greater changes in MAP, RBF, and RVR in septic mice than in controls. Among the vasoconstrictor challenges, only NE ameliorated the decrease in GFR 14 h after LPS injection. The in vivo results demonstrate that the renal microvasculature displays a normal or enhanced reactivity to constrictor agents as compared with nonrenal circulatory beds. Such responsiveness may contribute to reduced RBF and GFR during endotoxemia.

Acute Kidney Injury↗

PubMed2004

Thromboxane receptor mediates renal vasoconstriction and contributes to acute renal failure in endotoxemic mice.

Sepsis is a major cause of acute renal failure (ARF) and death. Thromboxane A2 (TxA(2)) may mediate decreases of renal blood flow (RBF) and/or GFR associated with LPS-induced sepsis. This study tested whether TxA(2) receptor blockade, with the use of TxA(2) receptor knockout (TP-KO) mice or a selective TP receptor antagonist (SQ29,548), would alleviate LPS-induced renal vasoconstriction and ARF. Under basal conditions, anesthetized TP-KO mice displayed a lower mean arterial pressure than wild-type (WT) mice (102 versus 94 mmHg; P < 0.05). RBF, renal vascular resistance (RVR), GFR, and urine flow did not differ among groups under basal conditions, suggesting little tonic influence of TxA(2) on renal TP receptors in health. In endotoxemic WT mice, 14 h after LPS (Escherichia coli LPS 8.5 mg/kg intraperitoneally), mean arterial pressure was reduced to 85 mmHg (P < 0.001), as were RBF (5.0 versus 9.3 ml/min per g kidney wt; P < 0.001) and GFR (0.38 versus 1.03 ml/min per g kidney wt; P < 0.001). Heart rate and RVR (71 versus 47 mmHg/ml per min; P < 0.05) increased. The decreases in RBF and GFR after LPS were attenuated in TP-KO mice versus WT mice (both P < 0.05). In both TP-KO and TP antagonist-treated mice, RVR remained stable in response to LPS versus WT mice that did not receive LPS. Delayed TP-antagonist treatment (12 h after LPS injection) ameliorated RBF and RVR but did not restore GFR. In other WT animals, TP-antagonist treatment for 2 h before intravenous LPS abolished the early renal vasoconstriction and alleviated the decrease in GFR. These results demonstrate that renal vasoconstriction during endotoxemic shock induced by LPS is mediated by TP receptors as indicated by pharmacologic blockade and genetic disruption of TP receptors.

Acute Kidney Injury↗

PubMed2004

Progression and regression in renal vascular and glomerular fibrosis.

End-stage renal disease (ESRD) is characterized by the development of fibrotic lesions in the glomerular, interstitial and vascular compartments. Renal fibrogenesis, a common complication of diabetes and hypertension, is a complex dynamic process involving several players such as inflammatory agents, cytokines, vasoactive agents and enzymes participating in extracellular matrix assembly, anchoring or degradation. The only available treatment today against chronic renal failure is dialysis or kidney transplantation, making thus ESRD one of the most expensive diseases to treat on a per-patient basis. An emerging challenge for clinicians, maybe the nephrologist's Holy Grail in the 21st century, is to stop definitively the decline of renal function and, if possible, to achieve regression of renal fibrosis and restoration of renal structure. Over the last 5 years, different approaches have been tested in experimental models of nephropathy with variable degree of success. In this review, we will focus on the mechanisms of the hypertension-associated fibrosis and the few recent studies that gave promising results for a therapeutic intervention.

Disease Progression↗

PubMed2003

Renal effects of omapatrilat and captopril in salt-loaded, nitric oxide-deficient rats.

Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received NG-nitro-L-arginine methyl ester (L-NAME, 20 mg x kg(-1) x d(-1)) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg x kg(-1) x d(-1)) plus L-NAME, or omapatrilat (80 mg x kg(-1) x d(-1)) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was approximately 90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2003

Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and matrix metalloproteinases.

Renal fibrosis is one of the major complications associated with the development of hypertension. The objective of the present study was to determine whether and by which mechanisms treatment with AT1 receptor antagonists makes possible the regression of renal vascular and glomerular fibrosis. Experiments were performed in the hypertensive model of nitric oxide (NO) deficiency in rats. After 4 wk of hypertension, mortality rates averaged 20%; the surviving animals displayed a decline of renal function (urine protein/creatinine, 1.89 +/- 0.63 versus 0.24 +/- 0.03 mg/mmol; creatininemia, 110 +/- 14 versus 38 +/- 2 mmol/L in hypertensive animals and control, respectively; P < 0.01) and an exaggerated gene and protein expression of TGF-beta, collagen I, and collagen IV (P < 0.001) within the renal vasculature associated with the development of glomerulosclerosis (sclerotic index, 2.26 +/- 0.29 versus 0.12 +/- 0.04; P < 0.001). In addition, activities of matrix metalloproteinases 2 and 9 were increased twofold in renal vessels and glomeruli (P < 0.01). Afterwards, losartan, an antagonist of angiotensin receptor type I, or hydralazine were administered in subgroups of hypertensive animals. After 1 wk of angiotensin II antagonism, collagen I, collagen IV, and TGF-beta gene and protein expressions were decreased and glomerulosclerosis was less marked (sclerotic index 1.04 +/- 0.45), whereas activities of metalloproteinases remained twofold higher than controls (P < 0.01). Hydralazine failed to improve renal function despite a similar degree of systolic pressure decrease. After 4 wk of losartan, the renal functional and histologic parameters were completely normalized, whereas they remained damaged in the hypertensive animals in which the mortality rate reached 85%. These data suggest that the progression of renal vascular fibrosis is a reversible process, at least in the NO deficiency model. The mechanism of the regression appears to be dual: inhibition of collagen synthesis due to AT1 receptor antagonism and activation of metalloproteinases that is probably associated with the degree of fibrosis independently of AT1 blockade.

Angiotensin Receptor Antagonists↗

PubMed2002

[Renal involvement in scleroderma].

Scleroderma renal crisis occurs most often during the first years of the disease, in patients with systemic sclerosis and evolving cutaneous lesions. Clinically, it is responsible for severe hypertension, sometimes associated with cardiac failure or neurological symptoms. Laboratory tests disclose rapidly progressive renal failure, and often signs of thrombotic microangiopathy. If performed (which is rarely the case), renal biopsy shows scleroderma-induced chronic vascular lesions, but also vascular lesions that are secondary to malignant hypertension. The cornerstone of treatment is blood pressure control using angiotensin converting enzyme inhibitors, often in association with other antihypertensive agents. It has to be started as early as possible, in order to optimise vital and renal prognosis.

Antihypertensive Agents↗

PubMed2002

[Vasoactive peptides and the development of renal sclerosis: contribution of transgenes].

Vasoactive peptides are implied in the development of renal sclerosis as evidenced by the efficiency of their antagonists in preventing glomerulosclerosis of experimental and human nephropathies. Genetically engineered models provide a new approach to investigate the mechanisms of the renal profibrotic actions of angiotensin II and endothelin. Overexpression of the human angiotensinogen and renin genes in rats induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed in mice. Transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[1]) and made hypertensive by induction of nitric oxide (NO) deficiency were used to study the renal profibrotic actions of vasoactive peptides. In this strain of mice, luciferase activity is an early index of renal fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were deficient in NO. The pharmacological blockade of angiotensin II and endothelin prevented the development of renal sclerosis without modifying blood pressure. Moreover, when the endothelin receptor antagonist was administered after the development of renal fibrosis, preformed glomerulosclerosis partially regressed. Acute administration of vasoactive peptides and TGF-beta in transgenic procol alpha 2[1] mice showed that the angiotensin II activation of collagen I gene requires participation and/or cooperation of endothelin and TGF-beta. Recent data suggest that the profibrotic actions of vasoactive peptides also need the activation of EGF receptor, ERK and rho kinase pathways in renal and vascular cells.

Angiotensin II↗