Correlation of morphological findings with functional reserve in the aging donor: role of the poly (ADP-ribose) polymerase

O’Valle, Francisco; Benítez, Maribel; Gómez‐Morales, Mercedes; Bravo, José A.; Osuna, Antonio; Moral, R. Del; Martín‐Oliva, David; Oliver, F. Javier

doi:10.1016/j.transproceed.2004.03.029

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…PARP-1 expression was inversely correlated with the time to recovery of renal function. PARP-1 induction in tubular cells was previously found in different experimental models of ischemic renal injury [19]–[22], and our group recently demonstrated PARP-1 expression in tubules of aged donors [17]. However, the present study of a large series of kidney transplant patients supports aclose relationship between delayed renal function and tubular nuclear PARP-1 expression.…”

Section: Discussionsupporting

confidence: 52%

“…For this reason, whereas moderate PARP activity protects cellular genome integrity, excessive PARP activation can lead to cell death from ATP depletion [14]–[16]. Our group previously demonstrated that PARP1 expression in tubules of aged donors correlates with functional reserve parameters (serum creatinine and time required to achieve effective diuresis) [17].…”

Section: Introductionmentioning

confidence: 99%

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Poly[ADP-Ribose] Polymerase-1 Expression Is Related To Cold Ischemia, Acute Tubular Necrosis, and Delayed Renal Function In Kidney Transplantation

et al. 2009

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Cold ischemia time especially impacts on outcomes of expanded-criteria donor (ECD) transplantation. Ischemia-reperfusion (IR) injury produces excessive poly[ADP-Ribose] Polymerase-1 (PARP-1) activation. The present study explored the hypothesis that increased tubular expression of PARP-1 contributes to delayed renal function in suboptimal ECD kidney allografts and in non-ECD allografts that develop posttransplant acute tubular necrosis (ATN).Materials and MethodsNuclear PARP-1 immunohistochemical expression was studied in 326 paraffin-embedded renal allograft biopsies (193 with different degrees of ATN and 133 controls) and in murine Parp-1 knockout model of IR injury.ResultsPARP-1 expression showed a significant relationship with cold ischemia time (r coefficient = 0.603), time to effective diuresis (r = 0.770), serum creatinine levels at biopsy (r = 0.649), and degree of ATN (r = 0.810) (p = 0.001, Pearson test). In the murine IR model, western blot showed an increase in PARP-1 that was blocked by Parp-1 inhibitor. Immunohistochemical study of PARP-1 in kidney allograft biopsies would allow early detection of possible delayed renal function, and the administration of PARP-1 inhibitors may offer a therapeutic option to reduce damage from IR in donor kidneys by preventing or minimizing ATN. In summary, these results suggest a pivotal role for PARP-1 in the ATN of renal transplantation. We propose the immunohistochemical assessment of PARP-1 in kidney allograft biopsies for early detection of a possible delayed renal function.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Poly[ADP-Ribose] Polymerase-1 Expression Is Related To Cold Ischemia, Acute Tubular Necrosis, and Delayed Renal Function In Kidney Transplantation

et al. 2009

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“…The intensity of the expression of poly(ADPribose) polymerase (PARP-1) in tubular cells (i.e., the activation of PARP-1 in conditions of tissue ischemia results in cell necrosis) was associated with time to effective diuresis (r = 0.386, p = 0.01), P creat three months after transplantation (r = 0.374, p = 0.013), and donor age (r = 0.408, p = 0.006). [12] Also in IgA nephropathy, Gutierrez et al showed that among 32 patients who have had an episode of macroscopic hematuria-induced ARF, 25% of them had not returned to baseline P creat six months after the episode. [13] These patients were older and had longer, but not more frequent, episodes of macroscopic hematuria and higher baseline P creat .…”

Section: Discussionmentioning

confidence: 99%

Histological Features of Acute Tubular Necrosis in Native Kidneys and Long-Term Renal Function

2008

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There are few studies on the relationship between the morphology of acute tubular necrosis (ATN) in native kidneys and late functional recovery. Eighteen patients with acute renal failure (ARF) who had undergone renal biopsy were studied. All had the histological diagnosis of ATN and were followed for at least six months. Clinical characteristics of ARF were analyzed, and histological features were semi-quantitatively evaluated (tubular atrophy, interstitial inflammatory infiltrate, interstitial fibrosis, and ATN). According to the maximal GFR achieved during the follow-up, patients were divided into two groups: complete recovery (GFR ≥ 90 mL/min/1.73 m 2 ) and partial recovery (GFR < 90 mL/min/1.73 m 2 ). Only 39% of the patients achieved complete recovery. Patients with partial recovery achieved their maximal GFR (63 ± 9 mL/min/ 1.73 m 2 ) 37 ± 14 months after ARF, a period of time similar to those patients with complete recovery (i.e., 54 ± 22 months). Patients with partial recovery had more severe ARF: oliguria was more frequent (90 versus 17%, p < 0.01), and they had higher peak creatinine (13.85 ± 1.12 versus 8.95 ± 1.30 mg/dL, p = 0.01), and longer hospitalization (45 ± 7 versus 20 ± 4 days, p = 0.03). No single histological parameter was associated with partial recovery, but the sum of all was when expressed as an injury index [4.00 (2.73-5.45) versus 2.00 (1.25-3.31), p < 0.05]. In conclusion, among patients with atypical ATN course, those with more severe ARF and tubuleinterstitial lesions are more prone to partial recovery.

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“…Significantly increased activity has been noted for persons over 100 years of age [167] and, more recently, in organs donated for transplantation from older donors [168]. However, in rats, inhibition of PARP activity with PJ34 has been shown to improve vascular endothelial dysfunction associated with aging [169].…”

Section: Does Chronic Inhibition Of Parp Carry Risks?mentioning

confidence: 99%

“…Such a local accumulation of ATP around the damaged site could serve as a signal to activate apoptotic cell death, which is an energy-dependent process [268]. It is also noteworthy that while PARP-1 knockout mice showed no major untoward consequences in their development [168,269], PARG gene deleted cells appeared to have an increased sensitivity towards DNA damage [270]. A similar deletion in Drosophila also showed progressive neurodegeneration with a strong accumulation of poly(ADP-ribose), especially in the central nervous system [271].…”

Section: Poly(adp-ribose)glycohydrolase (Parg)mentioning

confidence: 99%

Poly(ADP-ribose)polymerase Inhibition - Where Now?

Woon

Threadgill

2005

CMC

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The poly(ADP-ribose)polymerases (PARPs) catalyse the transfer of ADP-ribose units from the substrate NAD(+) to acceptor proteins, biosynthesising polyanionic poly(ADP-ribose) polymers. A major isoform, PARP-1, has been the target for design of inhibitors for over twenty-five years. Inhibitors of the activity of PARP-1 have been claimed to have applications in the treatment of many disease states, including cancer, haemorrhagic shock, cardiac infarct, stroke, diabetes, inflammation and retroviral infection, but only recently have PARP-1 inhibitors entered clinical trial. Most PARP-1 inhibitors mimic the nicotinamide of NAD(+) and the structure-activity relationships are understood in terms of the structure of the catalytic site. However, five questions remain if PARP-1 inhibitors are to realise their potential in treating human diseases. Firstly, the consensus pharmacophore is a benzamide with N-H conformationally constrained anti to the carbonyl-arene bond but this is also a "pharmacophore" for insolubility in water; can water-solubility be designed into inhibitors without loss of potency? Secondly, some potential clinical applications require tissue-selective PARP-1 inhibition; is this possible through pro-drug approaches? Thirdly, different diseases may require therapeutic PARP-1 inhibition to be either short-term or chronic; are there potential problems associated with chronic inhibition of this DNA-repair process? Fourthly, PARP-1 is one of at least eighteen isoforms; is isoform-selectivity essential, desirable or even possible? Fifthly, PARP activity can be inhibited in cells by inhibition of poly(ADP-ribose)-glycohydrolase (PARG); will this be a viable strategy for future drug design? The answers to these questions will determine the future of disease therapy through inhibition of PARP.

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Correlation of morphological findings with functional reserve in the aging donor: role of the poly (ADP-ribose) polymerase

Cited by 7 publications

References 11 publications

Poly[ADP-Ribose] Polymerase-1 Expression Is Related To Cold Ischemia, Acute Tubular Necrosis, and Delayed Renal Function In Kidney Transplantation

Poly[ADP-Ribose] Polymerase-1 Expression Is Related To Cold Ischemia, Acute Tubular Necrosis, and Delayed Renal Function In Kidney Transplantation

Histological Features of Acute Tubular Necrosis in Native Kidneys and Long-Term Renal Function

Poly(ADP-ribose)polymerase Inhibition - Where Now?

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