Kim S^1,2, Jung ES¹, Lee J³, Heo NJ^1,4, Na KY^1,2, Han JS¹.

Korean J Intern Med. 2017 Mar 18. doi: 10.3904/kjim.2016.131. [Epub ahead of print]
DOI: 10.3904/kjim.2016.131

 

Кол­хи­цин мо­жет пре­пят­ство­вать про­грес­си­ро­ва­нию за­боле­ва­ний по­чек за счет сво­е­го ан­ти­фиб­ро­зи­ру­ю­ще­го и ан­тиа­по­пто­ти­че­ско­го дей­ствия.

 

ПРЕДПОСЫЛКИ/ЦЕЛИ

Кол­хи­цин — из­вест­ный пре­па­рат для ста­би­ли­за­ции мик­ро­тру­бо­чек, ис­поль­зу­е­мый для сни­же­ния сте­пе­ни по­вре­жде­ния тка­ней. Под­твер­жде­ния, что это эф­фект за­ви­сит от до­зы, нет. Мы изу­чи­ли ан­ти­фиб­роз­ное и апо­птоз­ное дей­ствие раз­лич­ных доз кол­хи­ци­на на мо­де­ли од­но­сто­рон­ней об­струк­ции мо­че­точ­ни­ка (ООМ).

МЕТОДЫ

Трид­цать шесть крыс Sprague-Dawley слу­чай­ным об­ра­зом раз­де­ли­ли на шесть групп. Две груп­пы, про­шед­шие ими­та­цию об­струк­ции мо­че­точ­ни­ка, по­лу­ча­ли пла­це­бо или кол­хи­цин (100 мкг/кг/сут). Че­ты­ре груп­пы ООМ по­лу­ча­ли пла­це­бо или три раз­лич­ные до­зы кол­хи­ци­на (30, 60 и 1000 мкг/кг/сут) в те­че­ние 7 дней. На 7-й день всех жи­вот­ных умерт­ви­ли.

РЕЗУЛЬТАТЫ

За 7 дней кол­хи­цин сни­жал им­му­но­ре­ак­тив­ность аце­ти­ли­ро­ван­но­го α-ту­бу­ли­на и фак­то­ра ро­ста опу­хо­ли-β в кор­ти­каль­ном ве­ще­стве по­чек с об­струк­ци­ей в за­ви­си­мой от до­зы сте­пе­ни. Кол­хи­цин умень­шал сте­пень ту­бу­ло­ин­те­сти­ци­аль­но­го по­вре­жде­ния и апо­пто­за и в кор­ти­каль­ном и ме­дул­ляр­ном сло­ях; вы­ра­жен­ность по­ло­жи­тель­но­го эф­фек­та бы­ла про­пор­цио­наль­на до­зе пре­па­ра­та. У жи­вот­ных ООМ бы­ла по­ни­же­на экс­прес­сия рас­щеп­лен­ной кас­па­зы-3, ED-1 и фиб­ро­нек­ти­на.

 

ВЫВОДЫ

Бы­ло по­ка­за­но, что пра­виль­но по­до­бран­ная до­за кол­хи­ци­на мо­жет ока­зы­вать ан­ти­фиб­ро­зи­ру­ю­щее и ан­тиа­по­пто­ти­че­ское дей­ствие при об­струк­ции мо­че­точ­ни­ка. Для при­ме­не­ния кол­хи­ци­на с це­лью предот­вра­ще­ния про­грес­си­ро­ва­ния за­боле­ва­ний по­чек в кли­ни­че­ской прак­ти­ке, ещё пред­сто­ит опре­де­лить его оп­ти­маль­ную до­зу.

 

 

Figure 1.
Comparison of (A) acetylated α-tubulin, (B) α-tubulin, and (C) tumor growth factor β (TGF-β) using colchicine treatment in ureteral obstructive kidneys. The expression of acetylated α-tubulin was increased in unilateral ureteral obstruction (UUO)-operated rats and was diminished in the cortical lesions of colchicine-treated UUO rats. The cortical expression of TGF-β was increased after UUO, and then gradually decreased during colchicine treatment. SV, sham-operated rats with vehicle; SC, sham-operated rats with colchicine treatment; UV, ureteral obstructive rats with vehicle; UC, ureteral obstructive rats with colchicine treatment. a p < 0.05, b p < 0.01.

 

 

Figure 2.
Pathologic findings in ureteral obstructive kidneys: glomerulosclerosis (periodic-acid Schiff [PAS] stain, ×400), tubulointerstitial damage (Masson’s-trichrome [MT] stain, ×100), and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL] stain, ×200). Tubulointerstitial damage and apoptosis were attenuated after colchicine treatment. Cx, cortical lesion; Med, medullary lesion; SV, sham-operated rats with vehicle; SC, sham-operated rats with colchicine treatment; UV, ureteral obstructive rats with vehicle; UC, ureteral obstructive rats with colchicine treatment. a p < 0.05, b p < 0.01.  

Effects of colchicine on renal fibrosis and apoptosis in obstructed kidneys

 

BACKGROUND/AIMS

Colchicine is an established drug for microtubule stabilization that may reduce tissue injury. No data were available that its effects may depend on the dosage of colchicine. We investigated the anti-fibrotic and apoptotic effects of various dose of colchicine in a unilateral ureteral obstruction (UUO) model.

METHODS

Thirty-six Sprague-Dawley rats were randomly assigned into six groups. Two sham groups were divided into a vehicle-treated or colchicine-treated group (100 μg/kg/day). Four UUO groups were treated with either vehicle or three different doses of colchicine for 7 days (30, 60, and 100 μg/kg/day, intraperitoneally). All of the animals were sacrificed on day 7.

RESULTS

Colchicine treatment diminished acetylated α-tubulin and tumor growth factor-β immunoreactivities in the cortical area of the 7-day obstructed kidneys, which was in dose dependent manner. Colchicine attenuated tubulointerstitial damage and apoptosis in both cortical and medullary area, and beneficial effects of colchicine therapy were dramatically shown at the higher dosage of colchicine. The expression levels of cleaved caspase-3, ED-1, and fibronectin were decreased in UUO animals.

CONCLUSIONS

We found that the proper dosage of colchicine may have anti-fibrotic and anti-apoptotic effects in obstructed kidneys. For clinical applications, an optimal dose of colchicine should be evaluated to maximize the prevention of renal disease progression.

 

KEYWORDS

Colchicine; Kidney; Microtubules; Ureteral obstruction