PMID- 10844611
OWN - NLM
STAT- MEDLINE
DCOM- 20000824
LR  - 20131121
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 57
IP  - 6
DP  - 2000 Jun
TI  - Renal response to repetitive exposure to heme proteins: chronic injury induced by 
      an acute insult.
PG  - 2423-33
AB  - BACKGROUND: Renal diseases are conventionally classified into acute and chronic 
      disorders. We questioned whether acute, reversible, renal insults may be induced 
      to incite a chronic scarring process, employing as an acute insult the glycerol 
      model of heme protein-induced renal injury. METHODS: Rats were subjected to 
      weekly injections of hypertonic glycerol for up to six months. Renal function was 
      serially determined, and the effect of such insults on renal histology and renal 
      expression of collagen and fibrogenic cytokines was assessed. RESULTS: After the 
      first injection of glycerol, which, expectedly, induced a prompt fall in the 
      glomerular filtration rate (GFR), subsequent injections encountered a remarkable 
      renal resistance in that the fall in GFR was markedly blunted. This resistance to 
      acute decline in renal function in rats subjected to repetitive injections of 
      glycerol was accompanied by less necrosis and apoptosis of renal tubular 
      epithelial cells after such injections. The attenuation in the fall in GFR in 
      response to repetitive exposure to glycerol-induced heme protein injury was 
      maintained for up to six months. A progressive decline in GFR appeared after 
      three months and was accompanied by histologic tubulointerstitial injury, the 
      latter assessed at six months. These kidneys demonstrated up-regulation of 
      collagen I, III, and IV in conjunction with increased expression of the 
      oxidant-inducible, chemotactic cytokine, monocyte chemoattractant protein-1 
      (MCP-1), and the oxidant-inducible, fibrogenic cytokine, transforming growth 
      factor-beta1 (TGF-beta1). The exposure of the kidney to a single injection of 
      hypertonic glycerol increased the expression of both cytokines some three to five 
      days following this exposure, while the exposure of NRK 49F cells in culture to 
      an iron-dependent model of oxidative stress also increased expression of 
      TGF-beta1 and collagen mRNAs. CONCLUSIONS: We conclude that this nephrotoxic 
      insult, repetitively administered, encounters a resistance in the kidney such 
      that the expected fall in GFR does not occur. However, with time, such resistance 
      is accompanied by a decrease in GFR, the latter associated with chronic 
      tubulointerstitial disease. Thus, a long-term cost is exacted, either along with, 
      or as a consequence of, such resistance. We suggest that chronic up-regulation of 
      such oxidant-inducible genes such as TGF-beta1 and MCP-1 contributes to 
      tubulointerstitial disease, and iron-mediated oxidative stress may directly 
      induce TGF-beta1.
FAU - Nath, K A
AU  - Nath KA
AD  - Nephrology Research Unit, Mayo Clinic/Foundation, Rochester, Minnesota 55905, 
      USA. nath.karl@mayo.edu
FAU - Croatt, A J
AU  - Croatt AJ
FAU - Haggard, J J
AU  - Haggard JJ
FAU - Grande, J P
AU  - Grande JP
LA  - eng
GR  - HL55552/HL/NHLBI NIH HHS/United States
GR  - R01DK47060/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Chemokine CCL2)
RN  - 0 (Hemeproteins)
RN  - 0 (Transforming Growth Factor beta)
RN  - 9007-34-5 (Collagen)
RN  - AYI8EX34EU (Creatinine)
RN  - PDC6A3C0OX (Glycerol)
SB  - IM
MH  - Acute Disease
MH  - Animals
MH  - Chemokine CCL2/metabolism
MH  - Chronic Disease
MH  - Collagen/metabolism
MH  - Creatinine/metabolism
MH  - Glycerol/administration & dosage/pharmacology
MH  - Hemeproteins/*pharmacology
MH  - Injections, Intramuscular
MH  - Kidney/*drug effects/metabolism/pathology
MH  - Kidney Diseases/*chemically induced/metabolism/pathology
MH  - Oxidative Stress/physiology
MH  - Rats
MH  - Transforming Growth Factor beta/metabolism
EDAT- 2000/06/09 09:00
MHDA- 2000/08/29 11:01
CRDT- 2000/06/09 09:00
PHST- 2000/06/09 09:00 [pubmed]
PHST- 2000/08/29 11:01 [medline]
PHST- 2000/06/09 09:00 [entrez]
AID - S0085-2538(15)47001-2 [pii]
AID - 10.1046/j.1523-1755.2000.00101.x [doi]
PST - ppublish
SO  - Kidney Int. 2000 Jun;57(6):2423-33. doi: 10.1046/j.1523-1755.2000.00101.x.